New Standard Stent-Thrombosis Definition Yields Comparable Event Rates for DES and Bare-Metal Stents

October 25, 2006

October 25, 2006 (Washington, DC) - A jam-packed auditorium here at the TCT 2006 meeting heard that under a proposed definition of stent thrombosis, established by a consortium of experts, the cumulative incidence of stent thrombosis might be no greater in patients treated with a drug-eluting stent than in those treated with a bare-metal stent.

These findings might surprise interventional cardiologists who have been bombarded with new information, including a number of meta-analyses recently presented at the World Congress of Cardiology 2006, previously reported by heart wire , suggesting that late stent thrombosis might be responsible for more death and myocardial infarction in patients who are treated with a drug-eluting stent.

The new definition for stent thrombosis presented today is the brainchild of the Academic Research Consortium (ARC). It is designed to eliminate variability in the definitions across various drug-eluting-stent trials, where it has previously been difficult, if not impossible, to compare the true rates of late stent thrombosis across different trials. ARC cochair Dr Donald Cutlip (Harvard Clinical Research Institute, Boston, MA), who had full access to the patient data and presented the findings during a special hotline session, analyzed results from four randomized trials—RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS—and showed that the risk of stent thrombosis, measured out to four years, in patients treated with the sirolimus-eluting stent was not statistically different from the risk observed in patients who received a bare-metal stent.

Based on this new definition, the incidence of stent thrombosis was not statistically different, reported Cutlip. "I think the definitions will give us a better indication of the risk; although we really shouldn't compare across the different trials, at least we'll know that, if we're looking at the results from two trials, they're reporting the same thing," Cutlip told heart wire .

The new ARC protocol should standardize the definition of stent thrombosis and provide consistency in the reporting of future trials, explained Cutlip. The Food and Drug Administration (FDA) has requested that the drug-eluting-stent companies use this new definition when they present data at an FDA meeting on stent safety in early December. The proposed ARC definition includes patients with definite/confirmed stent thrombosis, probable stent thrombosis, and possible stent thrombosis.

Also known as the Dublin Definitions

The independent analysis of data from the four Cordis-sponsored trials, conducted by the Harvard Clinical Research Institute and using the new definition of stent thrombosis, showed no excess of stent thrombosis with the drug-eluting stent compared with the bare-metal stent. Using the per-protocol definition of stent thrombosis, the cumulative incidence of stent thrombosis was 1.2% in the sirolimus-eluting-stent arm and 0.6% in the bare-metal-stent arm at four years. Using the new definition, stent thrombosis was 3.5% in the drug-eluting-stent arm and 3.3% in the bare-metal-stent arm. Evaluating only definite or probable stent thrombosis, similar results were observed: 1.7% risk of thrombosis in the bare-metal-stent arm and a 1.5% risk of thrombosis in patients treated with the sirolimus-eluting stent at four years.

A similar analysis, using data pooled at the patient level from Medtronic's Endeavor I, II, and III studies, as well as its continuing access registry, was also conducted. The proposed definition resulted in higher overall rates of stent thrombosis, but with higher event rates in the bare-metal-stent arm. Cutlip said the overall increase is driven mostly by increased late and very late "possible" events, with rates of definite or probable events similar to those from previous reports based on the protocol definitions.

Members of the ARC met earlier this year in Washington, DC, and more recently in Dublin, Ireland. The new ARC protocol, previously called the "Dublin Definitions," defines stent thrombosis as definite when confirmed by angiography or when pathologic confirmation of acute thrombosis in ACS patients is made. Probable stent thrombosis is defined as any unexplained death within 30 days or as target vessel MI without angiographic confirmation of thrombosis or other identified culprit lesion. Possible stent thrombosis is defined as unexplained death after 30 days.

With previously conducted trials, stent thrombosis was defined as having occurred more than 30 days' postprocedure in a target vessel that had not undergone revascularization after the procedure. In patients who had target lesion revascularization (TLR), either PCI or CABG, before a thrombosis, the event was not considered late thrombosis in the per-protocol study definition. According to Cutlip, this did not take into account the full thrombosis risk and likely favored bare-metal stents, which are older and have greater rates of TLR. In the analysis of the Cordis-sponsored trials, when investigators included stent thrombosis occurring very late in patients who underwent TLR, the rates of stent thrombosis were similar with bare-metal and drug-eluting stents.

Dr Bram Zuckerman, director of the FDA's division of cardiovascular devices, who participated in the panel discussion during the hotline session, said the data were reassuring but noted the independent analysis involved patients participating in clinical trials, all with clinical indications for drug-eluting stents. As a result, the risks might be quite different in the real world, where stents are often used off-label. Moreover, he said that the FDA will continue to follow the issue of stent thromboses closely because a "signal is there" and that the agency will assess the risk/benefit ratio in greater detail at the upcoming panel meeting in December.

Industry raises some concerns . . .

Dr Campbell Rogers, the chief technology officer for Cordis, said during the hotline session that although the definitions are never going to be perfect or acceptable to everyone, the proposed definitions were created with the input of the Cardiovascular Research Foundation, Harvard Clinical Research Institute, Duke Clinical Research Institute, the FDA, interventional cardiologists, and representatives from the major stent manufacturers. Moreover, the ARC protocol called for device companies to provide raw patient data to independent sources so that the data could be analyzed in accordance with the new definitions, something Cordis and Medtronic have done and that Boston Scientific, with its Taxus stent, plans to do.

"It is really incumbent on all device manufacturers to take that step so that we can reassure people about transparency and the safety of devices," said Rogers.

Another cardiologist who recently made the move to industry, Dr Donald Baim, executive vice president and chief medical and scientific officer at Boston Scientific, told heart wire that there was still was some "definitional instability" with the ARC recommendation. Baim questioned whether or not patients who have undergone TLR should be censored. In addition, the inclusion of possible stent thrombosis, which considers any unexplained death after 30 days to be stent thrombosis, is an issue.

"I think one of the questions is whether or not this new 'possible' definition of stent thrombosis should be lumped together with definite and probable," said Baim. "There is every indication that the possible thromboses occur equallyin both groups, and that they're just deaths, which we know occur in 1.5% per year of coronary disease patients."

"I think there are some nuances to the ARC definitions," added Baim. "They've been proposed, they haven't been published, they haven't been peer reviewed, and that will be a topic for discussion at the FDA meeting. We are going to present our data in every possible way. The definite and most probable definitions of stent thromboses remain our most robust analyses."

According to Dr Gregg Stone (Columbia University, New York, NY), the only stent thrombosis definition that matters is one that takes into account definite stent thrombosis only.

"Unless you see it angiographically, or God forbid, at autopsy, we don't know that it really occurred," Stone told heart wire . "You're presuming it. [By] restricting your analyses to definite stent thromboses, you're clearly missing some events, but as you broaden the umbrella, you're going to add a lot of noise. That's the problem with one approach vs the other approach. I am personally of the belief that we should look at definite stent thromboses as the number we need to report. However, we need to shift away from stent thromboses to the totality of outcomes for the patient, to look at the overall benefit, to look at the overall risks. On the safety side, we definitely need to look at death and myocardial infarction, which will give an overall picture of how a patient will respond to a particular device in terms of being free from major adverse events."

The complete contents of Heart wire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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