Durham, NC and Basel, Switzerland - Just in time for the FDA review of drug-eluting stent (DES) safety later this week, an observational study has been published online December 5, 2006 in the Journal of the American Medical Association providing some last-minute insights into the risk of death or MI among DES recipients who stop their clopidogrel vs those who don't [1]. But at least one expert cautions against "leaping" to a new standard of care without definitive proof.

Interventional cardiologists have repeatedly voiced their confusion over just how long they should be prescribing dual antiplatelet therapy in DES-treated patients but have had little in the way of data to guide their decisions.

Now, a new study by Eric L Eisenstein (Duke Clinical Research Institute, Durham, NC) et al has found that patients treated with DES who were no longer taking clopidogrel at six or 12 months face a significantly higher risk of death or MI over 24 months of follow-up than do patients still on clopidogrel at these time points.

If you have a DES, and until we get new data, you'd be wise to continue on clopidogrel and to restart it if you've been stopped.

Dr Robert Califf (Duke University), senior author on the study, emphasized to heartwire that randomized clinical-trial data are urgently needed, but Califf, at least for now, says that the findings should help guide clinical choices and encourage patient compliance. "If you have a DES, and until we get new data, you'd be wise to continue on clopidogrel and to restart it if you've been stopped. The fundamental statement I can make is that if you received a DES you should remain on clopidogrel indefinitely, or until new data tell us otherwise."

Also appearing in print this week are the oft-cited BASKET-LATE results that, as reported by heartwire, were the first to truly cement concerns about the hazards of stopping dual antiplatelet therapy at six months post-DES implantation. The BASKET-LATE study, available online, will be published in the December 19, 2006 issue of the Journal of the American College of Cardiology [2].

According to Califf, Eisenstein et al's study will be presented to the FDA Circulatory System Devices Panel meeting by coauthor Dr David Kong (Duke University) during the FDA's DES hearing—the fact that the data are now published should help the findings pack more of a punch, Califf said.

"These are very unbiased data," he stressed. "No company paid for this, it wasn't from a study designed to look at the problem: these are real patients in our practice that we've followed over time. Everyone needs to understand that these are very imperfect data and we need more data, but we think patients should be alerted enough so that they really take the initiative to get on clopidogrel if they need to be. People need to keep looking at this issue, and the answer may be modified as better data come in, but when you combine what we found with what the BASKET-LATE trial showed, they look pretty much the same."

Eisenstein et al looked at all patients treated with PCI and stenting between January 1, 2000 and July 31, 2005, with follow-up at six, 12, and 24 months. In all, 3165 patients received bare-metal stents and 1501 received drug-eluting stents. At six and 12 months, surviving patients who hadn't had an MI or revascularization procedure were divided into groups based on type of stent and whether or not they were taking clopidogrel at that time point.

After 24 months of follow-up, Eisenstein et al report that DES-treated patients who were event-free at six months and still taking clopidogrel at that time were significantly less likely to have died or suffered an MI when compared with DES-treated patients not taking clopidogrel; however, no such differences were seen among bare-metal-stent-treated patients on or off clopidogrel. When the same analysis was conducted based on clopidogrel usage in event-free patients at 12 months, again, clopidogrel usage predicted lower rates of death or MI in DES-treated patients at 24 months, but was not relevant to the bare-metal-stent analysis.

"I think the two most surprising aspects that we found are, first, the magnitude of the difference between the DES groups on clopidogrel and off clopidogrel, and second, that the signal remains for the duration of the study," Califf commented.

He was careful to point out that while the study does not directly compare DES with bare-metal stents, it should at least give clinicians some sobering food for thought when determining the implications of stent choice. Given the fanfare that first accompanied DES onto the market, clinicians may not have entertained the possibility that a bare-metal stent could actually be safer than drug-eluting stent if clopidogrel isn't maintained long-term. Indeed, while the authors are careful to point out that they did not factor in bleeding and other risks related to long-term clopidogrel use, at least in terms of death and MI, a bare-metal stent with or without clopidogrel was the safer choice than a DES without clopidogrel in their study. "The best-looking treatment in our data was DES plus clopidogrel; the worst-looking treatment was a DES without clopidogrel," Califf explained.

In the US we shouldn't leap to a new standard of care without more definitive proof that long-term clopidogrel is safe and effective.

Dr Gregg Stone (Columbia University, New York), commenting on the results of the study for heartwire, observed, "These are intriguing data but by themselves should not be used to change the standard of care for clopidogrel usage after DES, for several reasons."

For one, Eisenstein et al's study was an observational study and therefore open to unmeasured confounders. "The event rates in the DES-plus-clopidogrel cohort were unexpectedly 'too' good, perhaps by chance," Stone suggested. Moreover, other similar studies have not found a reduction in late stent thrombosis with long-term clopidogrel in DES-treated patients. In addition, long-term clopidogrel carries an approximately 1% major bleeding risk per year, said Stone, citing the CURE, CREDO, and CHARISMA trials. Finally, he noted, "The cost of prolonged or lifelong clopidogrel for all DES patients would be enormous."

In all, Stone summarized, "This is an interesting article with data certainly supporting the performance of an adequately powered randomized trial, but in the US we shouldn't leap to a new standard of care without more definitive proof that long-term clopidogrel is safe and effective."

Eisenstein et al's findings extend those of the BASKET-LATE study, which will also no doubt feed the FDA panel's deliberations later this week. As reported by heartwire, lead author Dr Matthias Pfisterer (University Hospital, Basel, Switzerland) first unveiled the trial results at the American College of Cardiology 2006 Scientific Sessions, suggesting at that time that for every 100 patients treated with a DES, five target vessel revascularizations (TVRs) would be averted, but at the price of three late deaths/MIs related to increased late stent thrombosis.

BASKET-LATE prospectively followed 746 consecutive patients who had initially been randomized 2:1 to either DES or bare-metal stents in the Basel Stent Kosten-Effektivitats Trial (BASKET) and who were event-free at the time their clopidogrel was stopped at six months. For BASKET-LATE, the patients were followed for death/MI for an additional year beyond the six-month mark. As Pfisterer et al report, rates of cardiac death/MI from day one were no different between DES- and bare-metal-stent-treated patients, but from seven to 18 months (after discontinuation of clopidogrel), these events were numerically higher in the DES-treated patients than in the bare-metal-stent group (4.9% vs 1.3%).

In multivariate analyses, DES was associated with a significantly increased risk for death or MI (hazard ratio 2.2; p=0.03), but also with a significantly reduced risk of restenosis-related TVR (hazard ratio 0.51; p=0.009). Of note, of the 65 events that occurred after clopidogrel discontinuation, 25% were deemed related to stent thrombosis. "Although differences were not significant in view of the relatively low overall frequencies, there was a two- to threefold increased rate of such late events in DES- compared with bare-metal-stent-treated patients," the authors write.

They conclude: "This prospective randomized comparison of DES vs BMS in a 'real-world' setting shows for the first time that the incidence of late cardiac death or nonfatal MI after the discontinuation of clopidogrel is greater in DES- as compared with bare-metal-stent-treated patients."

Elaborating to heartwire, Pfisterer put the findings in context, noting that the difference in late clinical events between the two groups was about 2.5%, apparently related to late stent thromboses. "In the Bern-Rotterdam registry [presented by Dr Peter Wenaweser at the World Congress of Cardiology 2006], the rate of angiographically documented late stent thrombosis was 0.6% per year over three years, a steady increase. So, the late-stent-thrombosis problem with DES is real, but the risk is low, ranging from 0.6% to 2.5%, similar to other side effects of drugs. This has to be balanced against the reduction of angiographic restenosis from about 20% to about 10%, or in our study a clinical-event rate reduction from 12.1% to 7.2%, which is a major benefit."

Another important point to remember, Pfisterer says, is that it is unknown whether prolonged dual antiplatelet therapy can actually prevent these events. "Such a therapy carries a risk of severe bleeding in the range of 1% to 2% per year, and costs too! We need more data. Still, there is a general feeling— not based on findings—that 12 months of treatment may be 'wise.' "

The late-stent-thrombosis problem with DES is real, but the risk is low.

Califf, along with Dr Robert Harrington (Duke University), wrote the editorial accompanying the publication of the BASKET-LATE results. In it, they point out that concerns about a risk of late stent thrombosis were raised within months of the market launch of the first DES—the Cypher sirolimus-eluting stent—yet companies manufacturing the devices have been slow to initiate the trials that would clarify the degree of risk and the appropriate duration of thienopyridine therapy once and for all.

BASKET-LATE, in combination with other observational findings, "have led us to the view that patients with DES should remain on clopidogrel and aspirin if at all possible until adequate studies are completed that, first, fully depict the trade-off of the benefit of DES with the risk of late thrombosis and, second, lead us to understand the time-oriented risk of stopping thienopyridine treatment over a course of years rather than months," Califf and Harrington write.

Commenting on the trial results to heartwire, Harrington, who is also a coauthor on the Eisenstein paper, declined to give any first-person opinions as to what he thinks the ideal duration of clopidogrel therapy might be because he will sit on the advisory panel at this week's FDA hearing. Instead, Harrington commented at length on the fact that the DES story exemplifies the fact that cardiovascular clinical research is driven largely by industry with the aim of gaining regulatory approval and less by academics and clinicians themselves.

Asked how he thought the research process could learn a lesson from the DES story, Harrington told heartwire: "The best system would bring together the major stakeholders—academics, private practitioners, government, industry, and even patients—to discuss and brainstorm around the major CV health problems that need to be addressed and to determine how best to tackle them, including how to fund," Harrington explained. "After that we need greater buy-in to the research process from both academics and practice clinicians, who need to understand that we have a professional and societal obligation to study new therapies and approaches."

That "buy-in" may prove immediately germane to the clopidogrel question tackled in the studies published this week: earlier this fall, 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/Johnson & Johnson has said it will be launching a 10 000-patient randomized cohort study comparing six months of dual antiplatelet therapy with 12 months of dual antiplatelet therapy in patients receiving the Cypher stent.

For the time being, DES instructions for use in the US specify at least three months of dual antiplatelet therapy for the Cypher stent and six months for the Taxus paclitaxel-eluting stent. Whether or not the BASKET-LATE results and the new data from Duke are enough to persuade the FDA's advisory panel to recommend extended clopidogrel will be at least one of the burning questions on the minds of clinicians and industry-watchers alike later this week.

Regardless of what the advisory panel recommends, Pfisterer, for one, said he has three wishes for regulators: "I hope the FDA will stimulate large independent prospective safety studies—one, to better define the size of the problem; two, to better identify patients at risk; and three, to provide information as to how to prevent late stent thrombosis in at-risk patients [potentially by stipulating] duration of antiplatelet therapy," he stated. "Industry will develop new DES with lower drug dosages, other release kinetics, and/or resorbable polymers, etc."