Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) and Dr Matthias Pfisterer (University Hospital, Basel, Switzerland) debated the merits of prolonged clopidogrel therapy on top of aspirin on day two of the EuroPCR meeting.

Arguing against the strategy of extending therapy beyond 12 months, Pfisterer pointed out that numerous studies suggest that the risk of stent thrombosis continues in a linear fashion, without any clustering of events when clopidogrel is stopped. In the Bern-Rotterdam analysis, for example, risk continued at a rate of 0.6% per year "in a straight line with no bumps" over three years. Likewise, data from four centers reported by Dr Antonio Colombo's (EMO Centro Cuore Columbus, Milan, Italy) group indicated that stopping thienopyridine therapy within the first six months was a strong predictor of stent thrombosis, but this association did not hold beyond the six-month mark, with nine of 16 patients who had stent thromboses after six months still, in fact, on clopidogrel at the time of their events.

Even in BASKET-LATE—Pfisterer's own study, credited with first stirring widespread concern for the stent-thrombosis problem—events occurred throughout the follow-up period. "If stopping clopidogrel had been the cause, we would have expected that most of the events would have occurred in the first 100 days after stopping," he said.

And if it is not necessarily helping, clopidogrel may harm, Pfisterer pointed out. Downsides include allergic reactions, problems of cost and reimbursement, and major life-threatening bleeding risk in the range of 1% to 2%, he said.

But Harrington, taking the opposing view, pointed to many of the same studies to argue that none of them necessarily excludes the possibility that clopidogrel and aspirin beyond 12 months reduced thrombotic events.

"You can tell this field is full of controversy because I'm going to use the exact same data to make the opposite point, that instead we should continue using clopidogrel post-DES, particularly in selected patients, for an indefinite period of time, at least until we have definitive clinical trials to prove otherwise."

Rather than confirming the futility of long-term dual antiplatelet therapy, studies pointing to a continuing accrual of events underscore the need for patients to stay on clopidogrel, Harrington argued. Some of the strongest evidence in support of this comes from a Duke study, by Eisenstein et al, which showed that patients at the lowest risk for death were those who received a DES and clopidogrel over 24 months of follow-up, whereas those with the highest risk—higher even than patients who received bare-metal stents with or without long-term clopidogrel—were those who received a DES but who stopped clopidogrel.

One new piece of evidence from outside the DES literature may help physicians make up their minds on extending dual antiplatelet therapy, Harrington suggested. This is the analysis by Dr Deepak Bhatt and colleagues (Cleveland Clinic, OH) published last week Journal of the American College of Cardiology, as reported by heartwire. They found that a so-called CAPRIE-like cohort, characterized as higher-risk secondary-prevention patients (with documented prior MI, ischemic stroke, or symptomatic PAD) who were treated with clopidogrel plus aspirin had significantly reduced rates of cardiovascular death, MI, stroke, or hospitalizations for ischemia, as compared with those who received placebo plus aspirin.

Harrington also pointed to bleeding analyses from this study, which suggested that bleeding excess, while more common with dual antiplatelet therapy than with aspirin alone, appears to occur primarily in the first few months of therapy and is similar to aspirin alone after nine to 12 months.

"If you are able to stay on the drug," said Harrington, "by the end of the year, the risk is very comparable. The notion that beyond a year you have continued accrual of bleeding risk is not seen by these data. These data would say if you are able to survive your early clopidogrel therapy that, in fact, you should tolerate the bleeding risk."

In his rebuttal, Pfisterer seemed impressed by the CHARISMA analysis: "These data, that long-term bleeding risk might decrease, are important and if true, then it may be good to continue clopidogrel therapy. But let's look at that in a randomized study." For now, he reiterated, "We don't have any data that longer-term treatment would really prevent late stent thrombosis, although there may be other indications for longer-term treatment, such as atherosclerosis."

Bhatt, who chaired the session, told heartwire that the CHARISMA analysis now influences his decision to continue dual antiplatelet therapy; his current approach is to use clopidogrel indefinitely, if patients can handle it financially and if they pass the "bleeding stress test" during the first 12 months of taking it.

"In the absence of evidence, if it seems like a patient is a candidate for long-term therapy, then I just tell him that he should be on this uninterrupted for the next year, and my own recommendation would be to be on it indefinitely until new data come up to change that opinion."

Bhatt cautioned, however, that his analysis, showing bleeding rates for clopidogrel plus aspirin and for aspirin alone to converge at around the nine-month mark, is appropriate only in patients who have not had a major, minor, or "nuisance" bleeding event. "It would be a mistake for people to interpret that slide as meaning that there is no increased risk of bleeding" with long-term clopidogrel," he warned.

In his concluding remarks, Harrington pointed out that both he and his adversary agree on the urgent need for randomized trial results to resolve the clopidogrel question in DES-treated patients. "This should be a wake-up call to the community as to the adoption of therapies without sufficient evidence. We really ought to be demanding full evidence for the things we are doing. It's also a call to the sponsors of drugs and devices that they really need to be developed in the context in which they are going to be used."