Drug-coated stents - hold your horses
Drug coated stents may indeed revolutionize cardiac therapy, but probably not for another 2 years.
By DrRich
At the Congress of the European Society of Cardiology in Stockholm in September, 2001, investigators reported early results from the RAVEL trial, a trial examining the efficacy of a drug-coated stent made by Johnson & Johnson. After their presentation, the audience (consisting largely of cardiologists from around the world) was unable to contain itself, and broke out into a loud and long applause. (While a few moments of polite applause is considered appropriate after a paper is presented in a formal scientific session, the sort of reaction displayed in this case is highly unusual.)
The excitement of the audience is understandable, because during a follow-up period of 210 days (7 months,) there was no restenosis in patients receiving the drug-coated stent in the RAVEL trial.
The RAVEL trial enrolled 238 patients, half of whom received standard stents, and half of whom received the J&J BxVelocity stent that is coated with sirolimus (an antibiotic that inhibits cell growth.) The stents were used in a blinded fashion - neither the doctors nor the patients knew whether they had received a drug-coated stent or a standard stent - and all patients were followed and reevaluated in exactly the same way. When the data were analyzed, patients with the standard stent had a 26% restenosis rate, while those with the sirolimus-coated stent had zero restenosis. Furthermore, patients receiving the sirolimus-coated stent had a significantly reduced rate (3.3% vs. 27.1%) of major cardiac events (i.e., events like heart attack or death) during the follow-up period.
To say the least, this result is absolutely remarkable. Restenosis, as Dick Cheney found out the hard way, remains the biggest problem with the use of stents, with an incidence of 20 - 30% at 4 - 6 months. (Click here for a quick and easy review of the problem of restenosis with stents.) In the past, reducing the rate of restenosis has been accomplished only in relatively small, incremental steps, by the use of various drugs and radiation therapy. Can it be that drug-coated stents will eliminate the problem, once and for all, in one fell swoop?
As it turns out, that now appears to be a possibility. While clinical investigators can be a churlish and skeptical lot, even those trying to reign in their enthusiasm were having a hard time avoiding an expression of wonder and hope after the RAVEL data was reported. More follow-up data needs to be gathered, they all point out, and a much larger randomized trial is being conducted in the United States to confirm these results, but still - anything approaching a 0% restenosis is revolutionary.
Indeed, if these results do hold up, the treatment strategy for coronary artery disease will have to be reevaluated in every aspect. For if we truly have a stent that opens blocked arteries and stays open, then the recommendations for treating diabetics (who have a significantly higher risk of restenosis than non-diabetics,) the indications for bypass surgery, and the indications for sticking with drug therapy only, will all have to be reexamined. In fact, one might argue that all the prior studies evaluating the relative merits of all these treatment approaches will immediately be invalidated.
So why should we hold our horses?
We need to keep our enthusiasm in check for three reasons. First, despite the remarkable early results with the sirolimus-coated stent, release of this product for general clinical use is not expected until 2002 in Europe, and 2003 in the United States. The regulatory bodies (in the U.S., this would be the FDA,) simply need more data before they will feel justified in making these stents available for widespread use.
Second, there is a broad, mostly unexpressed feeling among cardiologists that the results presented this week in Stockholm are simply too good to be true. The RAVEL trial enrolled a relatively small group of patients, and the follow-up time is still brief. What will happen in larger groups of patients, and with longer follow-up times? An important complication that occurs on average, say, in 1 of 1000 or even 1 of 100 patients, could easily not occur in such a small group, and would then go undetected. When you've got a revolutionary product like this - a product that, when released, will rapidly be used in tens of thousands of patients - it is especially important to try to understand even the relatively uncommon complications. A much larger randomized trial with the sirolimus-coated stent (the SIRIUS trial, which has enrolled over 1100 patients) is being conducted in the U.S. to try to confirm the results of the RAVEL trial, and to look for lower-incidence complications than the RAVEL trial could have detected.
Finally, there is some legitimate concern among scientists that the sirolimus-coated stent may not be preventing restenosis, but only delaying it. Sirolimus works by inhibiting the overgrowth of the endothelial cells (the cells that line the blood vessels) that often grow into the opening of the stent and close it off. However, after a standard stent is placed, a thin coating of endothelial cells is supposed to grow over the stent to protect it from clotting. If sirolimus not only inhibits the overgrowth of endothelial cells, but also inhibits the "protective coating" growth of these cells, there may be late restenosis due to the clotting of blood within the stents. Until 1 - 3 years of follow-up is documented, we will not know the ultimate re-stenosis rate with these drug-coated stents.
The bottom line: the early results with the sirolimus-coated stent are remarkably encouraging, far better than anyone could have realistically hoped. While the slow churning of the regulatory bureaucracy occurs, scientists will have the opportunity to measure whether these early results will hold up over the longer term.
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