Washington, DC - The drug-eluting-stent (DES) mood at last week's TCT 2006 meeting was upbeat—quite the opposite of the DES doom and gloom that characterized September's WCC 2006 in Barcelona. As reported by heartwire, new DES meta-analyses unveiled at the TCT meeting showed no increased risk of death/MI with DES in the pivotal trials of the FDA-approved devices and, in fact, if the new proposed definitions are accepted, no increased risk of stent thrombosis at all, compared with bare-metal stents.

Cardiologists who attended the meeting point out that the cheerful message from the TCT meeting is hardly surprising at a meeting backed heavily by industry. And, while reassuring, the new data have left many physicians puzzling over what to tell their patients and how to translate what they've learned in their day-to-day practice.

Dr David Cohen

"I think there's more optimism heading out of the TCT meeting than there was leaving the [WCC]," Dr David Cohen (Saint Luke's Mid America Heart Institute, Kansas City, MO) told heartwire. "The main issue that I think came out fairly clearly is that if one looks particularly at the approved on-label indications for DES, while there may be a small excess of late thromboses—and I think that still is a little controversial—it looks like that effect may counterbalance some earlier harm that may relate to treating the restenosis. So that the net effect in these on-label indications really looks to be reduction in restenosis with no substantial excess of death or MI."

Dr Gregg Stone

Dr Gregg Stone (Columbia University, New York, NY), TCT course director, also had a sanguine view: "I think most people at the TCT meeting left with a balanced view that every medical device or drug has advantages and side effects and it's always a matter of whether the advantages outweigh the side effects. The vast majority of people who were present left the TCT meeting feeling that preventing restenosis is a laudable goal that we've been working toward for 30 years, and that is within sight. We have a low-frequency adverse event that we have to deal with, and rather than throwing out the baby with the bathwater, it's time to deal with this adverse event with better next-generation devices. But in the meantime, the current magnitude of the problem does not warrant losing the opportunity to prevent restenosis in tens of thousands of patients."

Dr Stephen Ellis

Others, however, hinted that the reassurances of DES safety at the TCT meeting might have swung too far in the other direction. "I think it's a little bit of a pendulum, to be honest with you," Dr Stephen Ellis (Cleveland Clinic, OH) told heartwire. "I think many of the attendees at TCT were not at the World Congress, where the mood was decidedly anti-DES. I think that in many ways the data presented at TCT might be viewed as a defense of DES and so it probably depends on whom you speak to. I personally think that stent thrombosis is an issue; it may have been somewhat overblown based upon the analyses that were presented at the World Congress, but it's still an issue that needs to be addressed and fleshed out."

Likewise, Dr Lars Wallentin (Uppsala Clinical Research Center, University Hospital, Sweden) called the TCT meeting a "mixed message."

"I think that the TCT meeting obviously is heavily sponsored by the companies that are producing all these stents, and most of the people presenting the data are also closely connected to the companies, so the information we got there was maybe a little bit of a counterattack to the data presented at the [WCC]. I think the general feeling among many people is that the truth is somewhere in between."

Analyst reports, which forecast a downturn in DES sales following the European meeting, seem buoyed by the TCT data. Prudential Equity Group increased its growth estimates for the manufacturers of the Cypher and Taxus stents after a survey of European cardiologists attending the TCT meeting suggested that DES usage was likely to "rebound" from a downturn over the past six months.

"The increases to our Taxus and Cypher estimates also reflect our survey finding that long-term safety data are the most important DES attribute overall; we believe this will benefit Cypher and Taxus," since they have the longest-term data so far, Lawrence Biegelsen writes in the Prudential report.

Just how big is too big?

Most experts agree that the data from the Cypher and Taxus meta-analyses are reassuring, but repeatedly, cardiologists interviewed by heartwire raised the same three concerns. First and foremost, the meta-analyses looked only at data from the company-sponsored randomized clinical trials, thus reflecting only patients for whom the devices are now indicated. Both were conducted by the Cardiovascular Research Foundation (CRF), the sponsor of the TCT meeting. Left unanswered are clinicians' niggling fears about real-world patients. Registry data presented at the TCT meeting and elsewhere are continuing to spawn debate over the true stent-thrombosis rate among patients treated off label, ranging from 0.2% per year to 0.6% per year in the now-infamous Bern-Rotterdam registry presented at WCC 2006.

"There does appear to be this small, somewhat-disquieting signal of late thromboses that is really there, and we don't know how much of an effect these are going to have and how long they're going to last," Cohen said. He notes that off-label use of drug-eluting stents hovers at about 60% of DES implanted. "I think we really don't have a good understanding of the problem in the large number of patients who get off-label drug-eluting stents. And if anything is still a real concern to me, that's the one."

Cohen also noted that while the death/MI rate balanced out between bare-metal stents and DES in the CRF meta-analyses, he wants to see the data on the types of MIs in both groups.

"There are MIs, and there are MIs," he explained. "And one of the concerns is whether the size of the MIs that are occurring in the different arms could be different. The bare-metal stents may be having more smaller MIs due to restenosis and the things that surround restenosis, whereas the DES are having more larger MIs that we know are the type that are caused by stent thrombosis. And could those somehow be masked in the way that the data are analyzed to date? The only way to tell that is to follow millions of patients for mortality, because eventually that will come out. And that's probably not going to happen."

Duration of risk, duration of drugs

The second issue is the duration of stent-thrombosis risk, experts told heartwire. Given the lack of long-term data, interventionalists are understandably squeamish about how long the risk endures. "We're not sure if this risk continues at the same pace forever," Ellis said. "And that would obviously make us all view things in a very different light."

Even Stone, who presented the CRF meta-analysis for the Cypher stent trials, pointed out that the so-called counterbalancing effect of reducing restenosis while increasing stent-thrombosis risk would swing against DES if the stent-thrombosis risk continued after the antirestenosis properties of DES vs bare-metal stents equalized.

Ever an optimist, Stone also sees this as an opportunity. "There is a problem with DES, but the meta-analyses were also consistent with the fact that if late stent thrombosis could be eliminated, DES offer the potential to reduce death and MI rates compared with bare-metal stents," he told heartwire. "So there's a potential upside, and I think industry hears and sees the issue and will be working diligently to respond with even safer products."

Dr Alaide Chieffo

In the meantime, operators must grapple with the third issue: duration of antiplatelet therapy. Pegged as one of the issues that will dominate FDA panel deliberations next month, the clopidogrel question also came up repeatedly during the TCT meeting and in subsequent interviews with heartwire. Adding fuel to the fire, a registry analysis presented at the TCT meeting by Dr Alaide Chieffo (San Raffaele Scientific Institute, Milan, Italy), with follow-up in 3021 consecutive DES recipients treated in Milan, Siegburg, and Naples, suggested that the greatest risk of stent thrombosis occurring with discontinuation of clopidogrel is during the first six months.

Other research at the TCT meeting explored whether testing for clopidogrel resistance, hypothesized to contribute to late stent thrombosis in DES recipients, might help identify patients at risk, while still more studies compared the effects on platelet inhibition of clopidogrel vs newer thienopyridines, like prasugrel. But as Cohen explained, testing for clopidogrel nonresponsiveness is premature.

"I saw some data at TCT that suggested that a variety of bedside platelet-aggregation assays can identify patients who are less responsive to clopidogrel, and these patients do seem to have, at least in several small studies, an enhanced risk of stent thrombosis," he told heartwire. "At this point, though, it's sort of a moot point to diagnose this if we don't have anything more we can offer these patients: we don't know whether increasing their clopidogrel dose will help. It might help to use some of these newer clopidogrel-like drugs that are being tested right now, but we don't have any proof of that, either."

Experts participating in panel discussions at the TCT meeting for the most part supported extending clopidogrel therapy to one year, something now supported in the European guidelines, which recommend six to 12 months of dual antiplatelet therapy post-DES implantation. But Stone points out that this strategy has no real support. "Safety and efficacy were proven in the randomized trials, with three months of clopidogrel use for Cypher and six months of clopidogrel use for Taxus, and we don't yet have any evidence that prolonged use decreases stent thrombosis," Stone argued. Bleeding risks and costs are two strong arguments against extending clopidogrel therapy, he added.

Dr William O'Neill

Indeed, the idea that clopidogrel cannot be a long-term solution was expressed repeatedly at the TCT meeting. During a press conference at the meeting, Dr William O'Neill (University of Miami, FL) suggested that interventionalists themselves should shoulder some of the blame.

"My own hypothesis is that we've changed the way that we're implanting stents from the bare-metal stents to the DES. In the bare-metal-stent era, we very frequently used high-pressure balloon inflations, maximally dilated the stents, fully opposed them against the vessel wall, and used IVUS guidance frequently. Now with DES I think—at least what I've noticed at our institution—is that people are becoming somewhat lackadaisical . . . and as a result, these DES are inadequately deployed, and when the clopidogrel is discontinued, there's the risk of stent thrombosis. We need to urge companies to go back and look mechanistically at this problem. . . . It's not a random event, and there has to be an explanation."

Coinciding with the TCT meeting, Cordis/J&J and Boston Scientific released press releases announcing that both companies would be funding the extension of existing multicenter registries in the hopes that bigger numbers will help them better understand the incidence of late stent thrombosis. Medtronic, whose Endeavor stent is not yet available in the US, announced the launch of an 8000-patient, multicenter randomized trial called PROTECT comparing the Cypher stent with the Endeavor, with stent thrombosis as its primary end point. Cordis also announced that it is extending out to eight years the clinical follow-up of patients in its SIRIUS, E-SIRIUS, and C-SIRIUS clinical trials, all of which were originally designed to end at five years.

Looking ahead for FDA guidance

For now, cardiologists are waiting with anticipation for the FDA panel meeting, December 7-8, 2006, where most hope to get a clearer understanding of the new Academic Research Consortium (ARC) stent-thrombosis definitions as well as a better snapshot of which patients stand to benefit the most from DES, with minimal risk. No one who spoke with heartwire predicted that anything drastic would happen to the already-approved DES, although many expect the approvability bar to be raised for as-yet unapproved devices. The chance of approved devices being yanked from the market is, in Stone's words, "extraordinarily unlikely."

Still, rumors abound as to who will sit on this FDA panel, since its makeup could have a profound effect on any resolutions adopted by the FDA.

"There are some very strong vested interests and some very strong biases, at least in my opinion, in various groups," Ellis commented. "And what you saw presented at TCT probably put the DES in their best light, and there's no doubt that there was strong vested interest by many of the people that presented data there. I think that also, on the other side, there's a large skepticism about the veracity of what is coming out of the pharmaceutical and device industry. Vioxx wasn't too long ago. . . . So you have that polarization of opinions, and I'm not sure where the FDA is going to come out."

Cohen thinks the FDA faces "a rather unique and challenging circumstance that they haven't reckoned with before," particularly since answers about risks in real-world patients won't be known for years, if ever. "Some people would say, if you have to study millions of patients for many, many years, then how could it possibly be worth knowing about? There may be some truth to that. The fear over this is that nearly a million people per year in the US are treated with these devices, so even a very small increase in mortality would result in unknown numbers of excess death. We do worry about that."

Thinking critically

Taken together, the impact of the WCC 2006 and TCT 2006 meetings seems to be healthy and spirited discussion, some rethinking of how DES are used, and in some cases, a modest scaling back of DES usage.

In Sweden, for example, a media frenzy ignited following the WCC 2006 presentations, fueled in part by a crude analysis of Swedish registry data that seemed to mirror stent-thrombosis rates seen in the Rotterdam-Bern registry. These were unadjusted data, Wallentin told heartwire, and published only in the Swedish-language press. "This story got a lot of attention, it was [picked up by] other media, and patients were very worried and calling continually for a few days asking if they could get their stents taken out."

Wallentin, after meeting with the Swedish medical groups and regulators, is now heading up a more scientific evaluation of the data and says the "media storm" has since died down. "There is a signal, but that's all we have so far. We've recommended that cardiologists should be restrictive in their use of DES and not use them in all comers, but in a more selective fashion, and that patients should continue on their antithrombotic medications and discuss this with their treating physician."

Ellis, likewise, acknowledges "a little bit of retrenchment" in his use of DES since WCC 2006 that he thinks is largely unchanged by news at the TCT meeting. "We are trying to be particularly careful when we put DES that the patients will be capable of taking Plavix long term," he said.

Cohen, too, estimates that DES in his lab has dropped back from where it was earlier this year, at 90% of all stents used, to somewhere in the low to mid-eighties. "We are thinking long and hard about it, but we are still using them, and we're using plenty," he said. "It's not much of a cutback, but it reflects at least that we are trying to think critically when we put one in—is this really the best thing for the patient? And that's probably a good thing."