The Device Industry's Rx Marketing Dilemma

The big news out of this year's TCT meeting in September wasn't really news at all. The final results of the SIRIUS clinical trial, assessing restenosis rates and other clinical measures of the sirolimus-coated drug-eluting stent (now being marketed in Europe by Cordis Corp. , a Johnson & Johnson operating company and soon to be available in the US) weren't all that different from the preliminary data previewed in May at the Paris Course on Revascularization. (See "For Drug-Eluting Stents, How Full is the Cup?" IN VIVO, May 2002 (Also see "For Drug-Eluting Stents, How Full is the Cup?" - In Vivo, 1 May, 2002.).)

The final results of SIRIUS, while not achieving the 0% in-stent restenosis and target vessel revascularization rates of earlier studies such as the FIM and RAVEL trials, still carried some very encouraging news. In a randomized trial that ultimately included just under 1,100 patients, Cordis' Cypher drug-eluting stent was shown to reduce restenosis rates by more than 90%, from 35.4% in the control group to 3.2% in the sirolimus group. A slightly smaller reduction was recorded in a sub group of in-segment restenosis, which came in at 8.9%, while certain explorations of other sub groups showed that drug-eluting stents were gradually less effective as lesion size grew larger, vessel diameter smaller, or the incidence of diabetes in the patient population group increased.

Still, all in all, this was good news all around. SIRIUS confirmed that drug-eluting stents are highly effective for a significant portion of the patient population. And if SIRIUS didn't quite match RAVEL and its perfect restenosis record, leading interventional cardiologists took the news in stride. Yes, the higher incidence of restenosis in selected sub groups provided reason to pause and reflect. Yes, though the results were good for lesions covered by the stent, there was incomplete suppression of restenosis at the stent margins, particularly the proximal margin, and the pharmacological agents seemed not to work well in gaps between the stents.

d: More studies and a deeper understanding of how and why drug-eluting stents work will be needed, said several interventionalists, now that RAVEL's perfect record is tarnished. At an evening symposium on drug-eluting stents, sponsored by Medinol Ltd. , Eberhard Grube, MD, one of Europe's leading cardiologists, cautioned, however, that RAVEL "set a very high standard that we won't ever match," adding, "Why we got 0% restenosis [in that trial], we don't really know. But we won't see 0% restenosis anymore." Martin Leon, MD, of New York's Lenox Hill Hospital, who directed the SIRIUS trial, noted the device's short-comings in selected patient groups but concluded his presentation of the trial's data saying, "Still, the overall conclusion is that SIRIUS shows consistent, if not absolute effectiveness in a much larger, more complex patient population." And Eric Topol, MD, of The Cleveland Clinic, in TCT's keynote address, called the trial "an extraordinary validation of the sirolimus stent."

At the same time, Cypher's less-than-perfect record gave hope to advocates for and manufacturers of other approaches to restenosis, such as sonotherapy, ultrasound, and brachytherapy—particularly since higher restenosis rates could be identified with specific patient sub groups, making new marketing targets easier to define. If drug-eluting stents aren't a cure-all, that must mean the door's open for other therapies, albeit in smaller patient populations, these companies reason. Some of the higher incidence of restenosis in the in-segment population may be due to errors of physician technique or length or placement of the stent, all fixable over time, but some just as certainly was due to the fact that certain patient populations just didn't respond to the drug-eluting stent. (One of the clinical trials presented was EuroSPAH, which looked at the effectiveness of the sonotherapy device of PharmaSonics Inc. in treating restenosis, and while the device didn't indicate a significant reduction in death or myocardial infarction versus a placebo group, it did show a dramatic decrease in revascularization.)

That's not to say that drug-eluting stents won't revolutionize interventional cardiology or the cardiovascular device industry—they are, notwithstanding any failings, simply too widely effective for too large a patient population. And as such, perhaps the most significant news at TCT was the release of the results, the day after the SIRIUS data was presented, of the TAXUS II trials, which assessed the clinical effectiveness of Boston Scientific Corp. 's taxotere-covered stent. Here, too, the results, while not perfect, showed significant reductions in restenosis rates.

So where does that leave us on the eve of US approval of drug-eluting stents? There are those who maintain that success in drug-eluting stents will still be a largely technological play: the major cardiovascular device companies continue to search for ever more effective pharmacological agents, agents with a different approach to restenosis than, say, the anti-proliferative approach of sirolimus. Recent clinical data seems to now point to inflammation, rather than proliferation, as actually being the critical factor in restenosis so companies are beginning to work on effectively targeting the body's inflammatory response. One such effort is underway in Israel through an alliance between stent-maker Medinol and Biorest Ltd., an Israeli biotech, in which Medinol has licensed for stents the use of a compound called biphosphonate to inhibit inflammation within coronary vessels. (See "Medinol: Can Technology Still Win In Stents?," in this issue.) Other companies are looking to improve drug efficacy through better stent structure—by designing stents specifically as drug delivery vehicles. Perhaps the most eagerly awaited work in this area will come from Palo Alto, CA-based Conor MedSystems.

Still, as clinical studies of different drug-eluting stents roll out, some drug coatings have already fallen by the wayside, such as Actinomycin-D, which Guidant Corp. had been working on. Meanwhile, the winners—those agents that prove effective in reducing restenosis—will likely show similar, if not precisely identical results to the Cordis and Boston Scientific stents, since anything less than the standards set by SIRIUS and TAXUS simply won't make it to market and, at the same time, it will be difficult to improve on the efficacy that the pioneering agents have shown.

That's why some industry officials believe the drug-eluting stent will increasingly become a sales and marketing play among medically similar products. In this era of evidence-based medicine, traditional criteria for device adoption—such as product design and physician comfort or feel—become less relevant than the data on clinical effectiveness that come out of large clinical trials. As with pharmaceuticals, the key to adoption isn't be how a device feels in a physician's hands or how it performs under his or her guidance during a procedure, but rather how effective the device is in achieving the clinical endpoints of its trial. And thus, like their counterparts in pharmaceutical marketing, drug-eluting stent companies may find that success will go to those that put together the largest, most effective sales force bringing ever more sophisticated analyses and arguments about ever smaller differences in clinical results.