Big Tent for Stent Trial Is All About Predictability of Results

Eight large product companies--including the top four drug-eluting stent (DES) companies, Abbott, Cordis, Boston Scientific, and Medtronic, as well as drug companies Bristol-Myers Squibb and Sanofi Aventis, makers and co-marketers of current anti-platelet blockbuster Plavix, as well as Eli Lilly and Daiichi Sankyo, co-developers of the much anticipated prasugrel—are collaborating on a large-scale, $100 million clinical trial assessing late-stent thrombosis.

That's interesting, we suppose, but hardly surprising and not likely to lead to any remarkable findings. Rather, it is the very predictability of the study’s likely results that is, we’d bet, what’s brought everyone to the table.

For one thing, the role of anti-platelet therapy following DES implantation has been aggressively studied for years and got a boost when the whole late stent thrombosis (LST) debate took off a couple of years ago. And every study, including several presented at this year’s TCT meeting in Washington DC where the news of the launch of the new study was announced, has shown the same thing: yes, patients face a much lower risk of LST when they stay on their meds for some period of time.

The new study may determine what the optimal Rx regimen is, but the notion that patients need to follow that regimen is what everyone’s betting will come out of the new study—and it’s hardly news. Only the direct opposite—that staying on an anti-platelet therapy has no impact on LST—would register as anything like a surprising result.

Moreover, what the WSJ called “an unusual display of collaboration,” among the companies—unusual, presumably, because they’re all fierce rivals in this space--is also hardly that. There’s no competitive issue at all here. All eight of the product companies are hoping and betting that the study results prove the clinical value of aggressive anti-platelet therapy—the drug companies, because they want to sell more drugs, the stent companies because they would like to show, once and for all, that the LST problem is more about the use of drugs than the use of stents and, more importantly, that the problem of LST is treatable with drugs.

Indeed, this could be an important study for both the Pharma and Device companies, but more so for the latter, if it conclusively demonstrates that physicians need not be concerned about putting their patients at risk by implanting a DES—if it proves to be the kind of large, definitive study that everyone called for when the LST crisis first broke.

But unless the study shows that one or two of the four stents being studied have substantially lower LST rates when the patient follows the appropriate drug regimen, there won’t be much of a competitive impact—this will be the rising tide that lifts all boats. And again, just based on earlier studies—LST has also been much studied in DES trials, particularly in the last two years—while head-to-head comparisons of various DES have shown different rates of stent thrombosis, they haven’t been meaningful.

In fact, if anything, the study’s risk, especially to DES companies, may lie not in findings that would show one stent superior to another, but just the opposite: findings that basically confirm everything we already know. The LST scare that burst onto the scene two years ago following data reported by Swedish researchers based on a Swedish patient registry was the device industry’s equivalent of Vioxx: a safety concern that caused havoc with what was once believed to be a blockbuster product category.

Drug-eluting stents are still the device industry’s one true blockbuster product. But the market has contracted—from $6 billion and growing a couple of years ago to $5 billion and stagnant—and reports from this year’s TCT suggest that while DES use has rebounded, that rebound has been mighty small.

The LST debate has been the leading cause of the contracted market. (Improvements in bare metal stents have also cut into DES sales, but only because of their implications in the LST debate.)

$100 million isn’t much spread among 8 companies, but only if, as stent companies hope, this kind of large, high-profile study conducted by a prestigious research organization, finally puts to rest the LST debate. If it doesn’t, if it simply raises calls for more studies looking at similar data—which is what’s happening a lot lately in cardiovascular circles—it could be a problem. --David Cassak

image of Taxus stent courtesy FDA via wikimedia commons.

While You Were ...

So what were you up to this weekend. Perhaps you were flying to Hamburg for the BIO shindig? Or throwing back a few half-pints at the (outstanding) Woking Beer Festival? Re-reading "The Naked and the Dead," maybe. Whatever your poison (ours was Tryst Brewery's Carronade IPA) we hope you had a good weekend.

• Novo Nordisk tells the Times: Exubera may have gone up in smoke, but inhaled insulin isn't dead yet. We'll be taking an in-depth look at the future of inhaled insulin in the next IN VIVO.


• Medical meeting season rumbles onward; at the American College of Rheumatology, on Saturday, NicOx presented further Phase III data from its '301' study of naproxcinod. Specifically, the company reported positive GI- and blood pressure-related safety and adverse event data for the drug candidate, a nitric oxide-donating form of naproxen that some analysts hail as a blockbuster alternative to the blighted Cox-2s. We've written extensively about naproxcinod here.


• Drug-coated stents are the new eggs. First they're good for you. Then they're bad for you. Now, apparently, good for you again. But manufacturers aren't holding their breath for a massive rebound in sales. The New York Times reports.


• Has Merck been punished adequately in the whole Vioxx debacle? Not everyone thinks so. Pharmagossip rounds up the usual suspects.

Cracks in Crucible of Evidence-Based Medicine Create "Climate of Calamity"

The real story emerging from this year's Transcatheter Cardiovascular Therapeutics (TCT) meeting in Washington, DC, is not the news per se regarding specific clinical trial results or new device technologies. Instead, it is the story behind the story that is making news.

Interventional cardiology has been built on the back of evidence-based medicine and, as the leading interventional cardiovascular conference, TCT--now in its 19th year--has long been the crucible for the unveiling of data from the randomized clinical trials and other studies that are the currency accounting for this specialty's historically rapid adoption of new device technology.

That methodology, however, has come under attack in the last year, creating what Martin B. Leon, MD, TCT's co-director, calls a "climate of calamity". The crisis coincides with the 30th anniversary of the procedure that has built the specialty--percutaneous coronary interventions--and is occurring in the industry's only true blockbuster product (at $5.5bn worldwide): drug-eluting stents.

The snowball that started the avalance was the release of data from a Swedish registry at last year's European Society of Cardiology meeting that raised concerns about DES safety in small numbers of cases due to problems with late-stent thrombosis. Other studies followed reporting similar problems, while still other trial results also challenged PCI's efficacy, e.g., the COURAGE study.

The result as evidenced by the tenor at this year's TCT: interventional cardiology is a specialty under attack. For the first time, both PCI procedures and DES stent usage are on the decline, in the latter's case, precipitously. According to Leon, PCI procedures have dropped by 10% in the last year, and DES penetration has fallen in the US from nearly 90% in January 2006 to around 60% in September 2007. Contributing to this crisis, in Leon's view: economic issues, the media, and regulatory challenges.

Leon and TCT co-director, Gregg W. Stone, MD, are using this year's conference as a pulpit to urge the specialty to essentially take a second look at evidence-based medicine, this time with a more critical eye. Indeed, one example they point to as indicating the need for a more balanced perspective, is that the most recent data from the same Swedish registry that caused much of the initial DES commotion, when released last month in Vienna at this year's ESC meeting, inexplicably showed improved patient outcomes with DES, not the increased risk found in the two prior years.

Nevertheless, the challenges to evidence-based medicine look to have a long-term impact on device innovation and product adoption. That was clear in a panel discussion following the release of generally positive data from the ENDEAVOR IV trial concerning Medtronic's Endeavor DES, which an FDA panel recently recommended for approval and is likely to be the next DES to hit the US market. Indeed, improved safety is seen as a potential advantage of Endeavor over the drug-eluting stents currently on the market, due in part to thinner struts and other design features. One area of concern: Endeavor showed higher late lumen loss than the Taxus DES, although that did not translate into any difference in restenosis. (Late lumen loss is used as a surrogate endpoint in clinical trials for restenosis.)

Despite Endeavor's apparent safety benefits, Mitchell Krucoff, MD, of Duke University Medical Center, one of the panelists, pointed to the higher late loss numbers as a concern, noting, "That would cause me to think twice about which drug-eluting stent to pull of the shelf when treating more complex patients."