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Drug Eluting Stent Overview Imaging & Diagnosis Center
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The following article provides an overview of drug-eluting stents (a.k.a "drug coated stents" or "medicated stents" or "DES") which gives a basic understanding of the history and mechanisms of these devices

For more in-depth information and late-breaking articles about drug-eluting stents, visit our Drug-Eluting Stent Center.

 


typical coronary stent
from the early 90's
    A Brief History of Stenting
The concept of the stent grew directly out of interventional cardiologists' experience with angioplasty balloons in the first decade of use (1977-87). Sometimes the wall of the coronary artery became weakened after balloon dilatation. Although the artery would be opened successfully using a balloon, in a small percentage of cases, the artery would collapse after the balloon was deflated -- sometimes this might not happen until the patient had been moved to the recovery room. Since there was no interventional "fix" available, the only option for this patient was emergency bypass graft surgery to repair the problem.

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.

  

cross section of
restenosed artery


Close-up of early
Palmaz-Schatz stent

The First Stents
One such device was the stent -- a metal tube or "scaffold" that was inserted after balloon angioplasty. The stent itself was mounted on a balloon and could be opened once inside the coronary artery. Julio Palmaz and Richard Schatz were working on such a stent in the United States; others in Europe were developing their own designs. In 1986, working in Toulouse, France, Jacques Puel and Ulrich Sigwart inserted the first stent into a human coronary artery. In 1994 the first Palmaz-Schatz stent was approved for use in the United States. Over the next decade, several generations of bare metal stents were developed, with each succeeding one being more flexible and easier to deliver to the narrowing.

A Persistent Problem
But while stents virtually eliminated many of the complications of abrupt artery closure, restenosis persisted. Although the rates were somewhat lower, bare metal stents still experienced reblocking (typically at six-months) in about 25% of cases, necessitating a repeat procedure. The interventional cardiology community also learned that restenosis, rather than being a recurrence of coronary artery disease, actually was the body's response to what Andreas Gruentzig called the "controlled injury" of angioplasty and was characterized by growth of smooth muscle cells -- roughly analogous to a scar forming over an injury.
  

Close-up of stent mounted on a balloon, circa 1995


A drug-eluting stent,
circa 2002
  
Development of Coated and Drug-Eluting Stents
More and more, the solution moved away from the purely mechanical devices of the 90's and toward pharmacologic advances that were being made. If interventional medicine, using the body's circulatory system as a "highway" to deliver therapy, worked with devices, it could also work with medicines. Physicians and companies began testing a variety of drugs that were known to interrupt the biological processes that caused restenosis. Stents were coated with these drugs, sometimes imbedded in a thin polymer for time-release, and clinical trials were begun.

Drug-Eluting Stent Basics
Sometimes referred to as a “coated” or “medicated” stent, a drug-eluting stent is a normal metal stent that has been coated with a pharmacologic agent (drug) that is known to interfere with the process of restenosis (reblocking). Restenosis has a number of causes; it is a very complex process and the solution to its prevention is equally complex. However, in the data gathered so far, the drug-eluting stent has been extremely successful in reducing restenosis from the 20-30% range to single digits. There are three major components to a drug-eluting stent:
  • Type of stent that carries the drug coating
  • Method by which the drug is delivered (eluted) by the coating to the arterial wall (polymeric or other)
  • The drug itself – how does it act in the body to prevent restenosis?

  

Artist's rendition of coated stent on balloon in artery

Interventional procedure being performed in the catheterization lab
  
In addition, there are several decisions made by the interventional cardiologist that result in a successful stent placement, whether of the drug-eluting or bare metal variety:
  • Correct sizing of the stent length to match the length of the lesion, or blocked area
  • Correct sizing of the stent diameter to match the thickness of the healthy part of the artery
  • Sufficient deployment of the stent, making sure that the stent, once placed at the optimum site in the blocked artery, is expanded fully to the arterial wall – under-expansion can result in small gaps between the stent and arterial wall which can lead to serious problems such as blood clots, or Sub-Acute Thrombosis (SAT)


Usually the sizing and the assessments of expansion are made by viewing the real-time angiogram in the cath lab, although some cardiologists also are using more detailed information obtained through intravascular ultrasound imaging.

Finally, in addition to aspirin, the patient must take an anti-clotting or antiplatelet drug, such as clopidogrel or ticlopidine (brand names Plavix and Ticlid) for a year or more after the stenting, to prevent the blood from reacting to the new device by thickening and clogging up the newly expanded artery (thrombosis). Ideally a smooth, thin layer of endothelial cells (the inner lining of the blood vessel) grows over the stent during this period and the device is incorporated into the artery, reducing the tendency for clotting.

 

  

Intravascular ultrasound image of stent in artery
Stent Wars
  
"Stent Wars"
The status and availability of drug-eluting stents are the subject of many legal disputes and other factors, which some time ago we labeled "Stent Wars". These devices were initially adopted so quickly that they doubled the world market for stents to $5 billion annually. In the post-stent-thrombosis era, that market has shrunk and, with newer second and third generation stents on the horizon, the flurry of activity among and between all of the competing device manufacturers will increase, as the companies fight not just for market share but, in some cases, survival.

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.


  
Outlook for Patient Care
While all eyes are on the issue of whether or not drug-eluting stents cause an increased incidence of blood clots (or thrombosis) the development of these sophisticated devices and the new wave of treatment options are further expanding the tools of cardiologists. Assuming the long term results are in line with the trials so far, the durability of interventional procedures to treat coronary artery disease non-surgically will have increased exponentially with the introduction of drug-eluting stents. The specter, possible complications (and expense) of repeat procedures will be vastly reduced. And diabetics, a patient population that previously has not seen great success with angioplasty and stent procedures, will be treatable with far more confidence.

And so advances the story of interventional cardiology, started 30 years ago on a kitchen table....

revised September 2008 by Burt Cohen

 

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