The Dilemma of Restenosis
A second problem soon became evident as well. Approximately 30% of all coronary arteries began to close up again after balloon angioplasty. By the mid-80's various radiologists and cardiologists were working on solutions to these problems, designing new devices in hopes they would provide more safety and durability to the procedures. Lasers, tiny "shavers", rotational "polishers" -- many tools were miniaturized to be delivered via catheter.

Close-up of early
Palmaz-Schatz stent

For several years, only two drug-eluting stents, the Cordis CYPHER™ sirolimus-eluting stent and the Boston Scientific TAXUS™ paclitaxel-eluting stent system, were approved by the FDA for sale in the United States (the Cypher stent in April 2003; the Taxus stent was approved a year later in March 2004) as well as the CE mark for sale in Europe. On February 1, 2008 the FDA approved a third DES: Medtronic's Endeavor stent which uses ABT-578, a drug made by its competitor Abbott. Although the Endeavor had been approved for sale in Europe since April 2005, Medtronic's entry into the lucrative U.S. market was the first new FDA-approved DES in four years.

Abbott had been developing its own Zomaxx stent in clinical trials, but cancelled development in the fall of 2006, opting instead to market the Xience stent, which it co-acquired as part of the Boston Scientific/Guidant/Abbott merger agreement. Boston Scientific has launched its "second generation" Taxus Liberte stent in Europe and is also going to be marketing the Xience, under the brand name "Promus". The Xience/Promus stent received FDA approval in July 2008 and has very rapidly become the leading DES in the United States.

Meanwhile, a number of new second and third generation stent technologies are in research, clinical trial phases, or have achieved marketing approval outside the U.S.. A new stent design by Conor MedSystems was approved in Europe in February 2006. Conor's CoStar stent utilizes a bioresorbable polymer to deliver the anti-restenosis drug, so that the after a few months of drug elution, the stent in effect becomes a bare metal stent -- which may eliminate the concern of late stent thrombosis present in permanent polymer stents. Conor was purchased by Johnson & Johnson in January 2007. A few months later, in a pivotal trial, the CoStar failed to show superiority to the Taxus and it has been sent back to the drawing board, perhaps to put a different drug in the polymer.

Taking a different approach, both Abbott and Germany-based Biotronik are testing a completely bioabsorable stent which will totally disappear after it has done its work. OrbusNeich received CE mark approval in 2005 for its Genous stent which, rather than using drugs to suppress excess tissue growth, utilizes an bio-engineered coating to attract a thin "all-natural" endothelial layer within hours. A number of other companies, such as Biosensors and Xtent, are working on other drug/polymer/stent combinations.

The major positive for drug-eluting stents is that all the approved devices have shown significant reduction of restenosis in clinical trials and in the "real world". DES have also shown dramatic reduction in reinterventions in diabetics as well -- this is a population that has been highly susceptible to restenosis in the past.

Stent Thrombosis
The issue of stent thrombosis also is being examined in more depth. In October 2003, the FDA issued a warning regarding cases of sub-acute thrombosis (blood clotting) with the CYPHER stent that resulted in some deaths. Upon further study, it seemed that the incidence of thrombosis was no greater than that with bare metal stents. For more information, read our article "Unravelling the Cypher".

There is some evidence, however, that drug-eluting stents may be susceptible to an event known as "late stent thrombosis", where the blood-clotting inside the stent can occur one or more years post-stent. While this has been seen rarely in both the Taxus and Cypher stent, thrombosis is extremely dangerous, fatal in over one third of cases. To prevent thrombosis, the above-mentioned post-stent antiplatelet therapy is very important and patients should not stop taking aspirin, Plavix or Ticlid without consulting with their interventional cardiologist.

The issue of late stent thrombosis, although discussed within the profession since drug-eluting stents were introduced, received widespread publicity at the September World Congress of Cardiology meeting in Barcelona when three European studies pointed to higher rates than had previously been seen (see our feature, "Problems Resurface with Drug-Eluting Stents" for detailed coverage). Late stent thrombosis was one of the major issues discussed at the 2006 TCT Meeting and the FDA scheduled a public meeting in early December 2006 on the issue. The conclusion was that more information was needed, especially about the use of devices in off-label settings, but that when used as directed, there did not seem to be greater risks of death or heart attack with drug-eluting stents.

For the first time since their introduction, the use of drug-eluting stents began to decrease slightly in late 2006, due to these concerns. Many cardiologists feel the issue has been overamplified, but many are also beginning to re-examine whether some patients will really enjoy that much of a benefit over the older bare metal stents -- especially patients whose blockages are judged to be at very low risk for restenosis. One issue that emerged was the need for patients to comply with their antiplatelet medications (aspirin and Plavix or Ticlid) -- current guidelines were changed to one year minimum, assuming no bleeding complications.

Developments in the "Stent Wars" can be fast and furious. Keep abreast of the constantly changing status of legal disputes and the various clinical trial results and controversies in our Drug-Eluting Stent NewsCenter.