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October 27, 2006 -- 5:19pm ET

Stent Wars Across the Atlantic: USA vs. Europe
I coined the term "Stent Wars" back in 2002, referring to the combat waged among the various device manufacturers. But at this year's TCT meeting, the specially-assembled "Stent Thrombosis Hot Line Session" revealed a new face of the stent wars: intercontinental cardiologists mano a mano!

For background on the issue, read Angioplasty.Org's report on September's European Society of Cardiology meeting in Barcelona. Basically several independent European analyses warned that potentially fatal blood clots caused by the stents (late stent thrombosis) occurred more frequently than previously reported, and that the effect persisted for years after implantation.

These reports and subsequent media coverage caused what Dr. Marty Leon, Director of the TCT, referred to as "the declining state of DES" (as well as the declining sales and stock prices of several companies). So a little after "High Noon" on Tuesday, October 24 over a thousand doctors, analysts, company reps, chief executives, and 78 (count'em) reporters gathered to watch what would happen on Main Street.

First the three European docs gave their presentations -- virtually the same ones they had given in Barcelona. Then TCT course directors, Drs. Marty Leon and Gregg Stone, presented two new sets of results: new analyses of the raw unpublished data from the original nine randomized clinical trials used to gain approval for both Cypher and Taxus drug-eluting stents.

Turns out that immediately following the Barcelona "firestorm", the stent manufacturers had given them the raw "patient-level" data from these clinical trials -- data that the same companies had previously declined to provide, for example, to one of the European presenters, Dr. Matthias Briel of Basel, Switzerland. Adding to the mix, these new analyses also used a new definition of stent thrombosis .

With "rawer" data and new definitions, the results of the U.S. analysis were quite different from the European. The conclusions, as stated in the front page headline of the following morning's TCT Daily: "Cypher/Taxus: No Increase in Thrombosis".

Then, one hour into the session, Marty Leon advanced to the microphone, metaphorically pulled off his surgical glove and tossed it down from the podium onto the floor in front of the panelists:

"I'm going to address this to our three European colleagues who must feel that they are under siege or on the defensive and that certainly is not the intent. Well maybe it is the intent a little bit.... I'm going to make two assumptions: one, that the companies would allow you to have access to the patient-level data we just presented; and two, that you analyze the data and you came up with conclusions that were similar to ours.... If those two assumptions were met...would each of you be willing to retract the conclusions that were represented at the ESC...?!"

The Europeans had been served. Will you retract, sir?!

Dr. Camenzind countered:

"The analysis I've shown you is constituted from data in the literature and officially presented. So it is not data that I received directly from the industry. So what we have to do, as the first thing, is we have to compare those raw data. Are they the same or are they not the same? If they are not the same, then we have to find out why they are not the same.

"Do we have input errors, typing errors in the literature or in the presentation of slides? This is a very very important issue. So before we go to any methodological issues, we have to be really sure of the raw data we are working off. Because only if we have the same raw data we will arrive at the same conclusion."

Typing errors?? Slide errors?? Was Dr. Camenzind actually postulating that the published results used to obtain approval of the Cypher and Taxus stents might differ from the raw data because of a faulty PowerPoint presentation? Certainly, he was exploring the possibility that the published reports of the raw data might be mis-stating the raw data itself.

Touché!

If you are lost here, so were many in the audience and on the panel (Dr. Sigmund Silber of Munich stated that the various results were "totally confusing".) A significant point: all the data in question above are from the nine clinical trials that were used to gain approval for the Cypher (RAVEL, SIRIUS, E-SIRIUS and C-SIRIUS) and Taxus stents (TAXUS II, TAXUS II, TAXUS IV, TAXUS V and TAXUS VI). The patients in these trials were done for "on-label" indications, meaning relatively straight-forward blockages, stable patients, expert cardiologists doing the procedures.

And the dispute between the U.S. researchers and Dr. Camenzind centered on analysis of the data, source of the data and integrity of the data.

But another and much larger issue was also surfaced in the other European studies. In the "real world", much stenting is done "off-label" -- sicker patients, more emergency situations, more complex multivessel disease, multiple stents. None of the patients included in these original clinical trials fit these definitions and it is in this "off-label" population that the European studies found even higher rates of stent thrombosis.

In the final minute of the meeting, Marty Leon deftly swiveled his attention from stage right to stage left and challenged Bram Zuckerman of the FDA:

"Why hasn't the FDA been more aggressive in insisting that every one of these companies do much closer and mandatory post-market surveillance registries, not just on the on-label indication, but on the off-label indication? If we had done this several years ago, we'd be well on our way to understanding this problem. I hate to be so aggressive, but this is a potential solution to the problem at least in the United States...."

Mr. Zuckerman quickly retorted:

"I would remind you, Marty, that both approved sponsors [Boston Scientific and Cordis] did initiate large post-approval device registries right after approval. Perhaps one question is, why haven't the sponsors made those data publically available?

"The real question under consideration though is how do we expand our knowledge base for the many thousands of patients who are treated with this device in so called off-label fashion? ...there are enough data published in the literature, such that the signal in the risk-benefit analysis that we saw with the FDA-approved [on-label] indications and meta-analysis today may not be extrapolatable to the so-called [off-label] real world."

Not extrapolatable to the "real world", so-called or not -- this is the crux of the problem: that the "readjuticated" data at the center of today's dispute may not be that relevant to current day-to-day practice, no matter which side of the Atlantic the analysis is done on. Reinterpreting the relatively tame cases done for the initial safety and efficacy studies is one thing. But trying to determine just what the extent of the problem is in the real world is another. And even the FDA agrees that a source of strong clear data for that determination is not immediately obvious.

I'll deal with these issues in a future post (as will the FDA -- they have called for a large public meeting on December 7-8 about these issues).

As for the post-approval data not being made public, as we were leaving the auditorium, I asked Boston Scientific's Chief Medical Officer, Dr. Donald Baim, if that was true -- if the company has kept the post-market registry results hidden? He said, "absolutely not -- they've got our data. Just look at ARRIVE I and ARRIVE II."

No one doubts that late stent thrombosis in DES exists. Even Boston Scientific issued a press release confirming it. The question is whether it is as significant as the European studies suggest, whether it is offset by reduced restenosis, and mostly, what it means for patients.

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