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Problems Resurface with Drug-Eluting Stents
September 9, 2006 (updated from September 4) -- Several presentations made at this year's World Congress of Cardiology / European Society of Cardiology annual meeting in Barcelona are once again highlighting some physicians' and patients' concerns about the long-term safety of drug-eluting stents (DES). Doctors are now viewing with heightened interest the problems of drug-eluting stent thrombosis, allergic inflammatory reactions, long term antiplatelet therapy and non-compliance.  

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Thrombosis is the price
for the success of
drug-eluting stents
-- European Society
of Cardiology

While the percentages of complications are relatively small, it is estimated that over 6 million patients have been treated with drug-eluting stents, so any observations of unanticipated outcomes are of critical importance. Reinforcing these concerns are the hundreds of comments from patients about drug and stent hypersensitivity reactions and procedural complications Angioplasty.Org has received on its Cardiology Patients Forum.

The studies presented this past week in Barcelona may well represent the avant-garde for how patients will be treated for coronary narrowing. It is possible that a new wave of protocols will increase the importance of patient selection and may involve a move back toward bare metal stents in certain situations, a screening regimen for allergic reactions, an increased period for antiplatelet therapy post-stent, the development of a second and third generation of bioabsorbable polymers or completely biodegradable stents -- all of which will have profound implications for patient care, as well as for the medical marketplace.

Three European Studies Highlight Problems
Dr. Edoardo Camenzind of University Hospital in Geneva, Switzerland gave a presentation titled, "Safety of drug-eluting stents: insights from meta analysis" in which his team looked at all the data gathered in the various clinical trials, and up to three years of follow up, for both the CYPHER (J&J/Cordis) and TAXUS (Boston Scientific) drug-eluting stents. They then compared outcomes with those of patients in the bare metal stent control groups. The Swiss study's results were dramatic: the incidence of death and heart attack was higher in patients who got drug-eluting stents -- 30-40% higher in the Cypher studies; about 5% higher in the Taxus group. Dr. Camenzind concluded that these increases were "the clinical presentation of stent thrombosis" -- a concern that has been expressed since drug-eluting stents were first introduced (2002 in Europe; 2003 in the U.S.).

A second Swiss meta-analysis of previously gathered data, headed by Alain J. Nordmann of University Hospital in Basel, showed no difference in cardiac death between drug-eluting and bare metal stents. However, it did show an increase in non-cardiac death from cancer, lung disease and stroke in the sirolimus (Cypher) stent groups, leading Dr. Nordmann to conclude, "Long-term follow-up and assessment of cause-specific deaths in patients receiving DES are mandatory to determine safety of patients receiving these devices."

A third study, from the ThoraxCenter in Rotterdam, tracked stent thrombosis rates in 8,000-plus patients enrolled in studies in Holland and Switzerland. Dr. Peter Wenaweser reported that over three years, the cumulative rate of thrombosis was 2.9%, but what was disturbing was that the rate was linear -- starting at 1.2% at 30 days (similar to bare metal stents) and then 0.6% each year thereafter. Unlike bare-metal stents, thrombosis did not seem to wane with time, but continued to increase at the same rate, confirming concerns that drug-eluting stents suppress cell growth too much in some individuals, opening the door to blood clots (thrombosis) which have serious consequences.

Thrombosis Concerns Not New
While the various media reports that have issued forth from the WCC meeting are, as usual, characterizing these data as new discoveries just announced, these concerns over drug-eluting stents were raised when these devices first became available. Angioplasty.Org reported in the fall of 2003 ("Unraveling the Cypher") of an U.S. FDA advisory over increased thrombosis. The advisory was modified a year later, stating that the adverse events were no greater than that seen with bare metal stents. In the interim, Boston Scientific introduced its Taxus paclitaxel-eluting stent and within a very short time, over 95% of the stents placed in the United States were of the drug-eluting variety. The numbers are smaller for Europe, where cost concerns over the more expensive stent has kept usage down a bit more.

Until recently, an almost lone voice of concern over thrombosis rates had been that of pathologist Renu Virmani, MD who has conducted autopsies on stent patients and found that drug-eluting stents showed delayed healing, where the thin endothelial layer of cells that would normally cover the metallic stent was uneven or non-existent. In a patient with both drug-eluting and bare metal stents, the bare stents had healed, but the drug-eluting stent had not and had, in fact, been the site of a thrombosis (blood clotting) which was the primary suspect as cause of death.

Perhaps a sign of the growing concern was that Dr. Virmani's talk at this year's EuroPCR interventional cardiology meeting in Paris garnered much interest and a full house. Her opinion about the widespread use of drug-eluting stents in the U.S., as she told Angioplasty.Org:

"I think it's a mistake in this country. What we have to do is make people aware. It's not for everybody. There's no need -- you don't die from a bare metal stent."

Dr. Virmani's concerns were echoed by well-known interventional cardiologist Dr. Ron Waksman of the Washington Hospital Center, who told Angioplasty.Org:

"I believe that drug-eluting stents are more thrombogenic than bare metal stents. I feel that there is some concern not only for me but for others in reconsidering twice why they should place a drug-eluting stent if they can still do it with a bare metal stent. I've always said that 80% of the people getting drug-eluting stents don't need them. Because they'll never restenose... It was only 20% that restenosed. The drug-eluting stents we just give to everybody.... In the U.S. there's an incentive, because you get more money if you use a drug-eluting stent."

Further confirmation of late stent thrombosis in drug-eluting stents was provided at the end of the World Congress in a surprise announcement by Taxus manufacturer Boston Scientific. The company revealed that an internal analysis of their own clinical trial data, covering the past four years and completed on June 24, 2006, had revealed a slightly higher, but statistically significant increase in late stent thrombosis with the Taxus paclitaxel-eluting stent. The company stated that it believed this was a "class effect" for all drug-eluting stents (Cordis and Medtronic both disagreed).

Allergic Reactions Seldom Reported
Another concern, perhaps related, has been that of hypersensitivity, or allergic reactions to drug-eluting stents. Hardly discussed because data is virtually nonexistent, this problem has been the subject of almost 200 postings on Angioplasty.Org's
Discussion Forum and was the subject of a Northwestern Medical Center study, published late last year in the Journal of the American College of Cardiology. It is thought that the numbers of patients who experience hypersensitivity reactions is not large, but that is difficult to determine because the syndrome is often misdiagnosed, thus the data collection process is flawed.

To remedy this, there are currently plans (as yet, unfunded) to develop some type of allergy test (it is thought that the allergic reaction is probably to the polymers). Such a test is very important because allergic reactions to the stent will probably result in an increased incidence of restenosis or thrombosis in those individuals. A danger, as Dr. Charles Bennett of Northwestern told Angioplasty.Org, is that If the stent allergy is misdiagnosed as an allergy to, for example, Plavix, then the patient may be taken off Plavix -- yet that might be the patient most at risk for thrombosis, a patient who, if anything, should be given more antiplatelet therapy, not less.

Problems with Long Term Antiplatelet Therapy
One of the biggest concerns of cardiologists has been what type and duration of antiplatelet therapy is optimal after drug-eluting stents. Early on in the bare metal stent experience, it became clear that the stent surfaces were thrombogenic: the foreign metal object attracted platelets, which tended to congregate and clot, forming a thrombus -- this thrombus could suddenly close off a major coronary artery, causing a heart attack, often fatal.

After much study, aspirin, combined with ticlopidine (Ticlid) and more recently clopidogrel (Plavix) became the primary antiplatelet drugs prescribed after stenting. These medications kept the platelets "slippery" while the artery healed and formed a thin layer of endothelial cells over the metal stent, removing the threat of thrombus. Four to six weeks seemed to suffice in the era of bare metal stents.

But drug-eluting stents work specifically by inhibiting or slowing cell growth, so the length of time for patients to be on antiplatelet therapy was lengthened. Currently the FDA recommends 3 months for the Cypher stent, and 6 for the Taxus. However, because of their concerns, most cardiologists prescribe Plavix for a year and aspirin for life; some even prescribe Plavix for life.

The problem is that, outside of the expense (Plavix currently costs $4/day), this therapy is not without side effects. A number of patients are allergic to Plavix, some quite substantially. Unfortunately, this is seldom determined, or even considered, prior to implantation of a drug-eluting stent. Our Discussion Forum topic on Plavix and Aspirin is filled with reports of allergic reactions and exasperated patients who are required to take a therapy that is making them ill -- the alternative being an increased risk of thrombosis and possible death.

Add to this the fact that these blood-thinning medications are not welcome if the patient requires surgery of any sort. Surgeons are very concerned over the uncontrolled bleeding that might ensue. In fact, patients are often told by their dentists to stop their Plavix and aspirin prior to oral surgery, with sometimes unintended and dire consequences.

As a result, perhaps due to cost or side-effects or other reasons, patient compliance with antiplatelet therapy is less than optimal. Dr. Antonio Colombo of Milan has done a study of this and is about to present a larger one -- he previously found that the "real-world" thrombosis rate was double that seen in carefully-monitored clinical trials, most likely due to premature withdrawal of antiplatelet therapy.

The Future of Drug-Eluting Stents
The problems stated above are not unknown and not new. And a number of companies have been developing innovative technologies that avoid some of the problems with the first generation DES. For example, Conor Medsystems has developed, and is now marketing in Europe, its CoStar stent, which has small recesses in the stent struts that hold a bioabsorbable drug-eluting polymer. In two months, the drug is eluted and the polymer has disappeared and the stent has become, for all intents, a bare metal stent. Other companies, like Biotronik of Germany and Switzerland, are testing biodegradable stents that will be completely absorbed into the body.

As for the current crop of devices, there have been rumblings in the U.S. that hospitals may be returning to bare metal stents for certain purposes. Dr. Virmani refers to a German study which looked at the diameter of the coronary artery being treated. She told us:

"No patient who has a vessel greater than 2.8mm should get a drug-eluting stent. If you look at the data that has come out of Germany, they showed no difference in restenosis between a drug-eluting stent and a bare metal stent if the vessel was greater than 2.8mm. In the United States, everybody uses a drug-eluting stent, irrespective of vessel size. I think it's a disservice to the patient."

With the advent of new devices, the development of tests for allergic reactions and more careful patient selection (who will benefit most from the use of drug-eluting stents), the trends in treatment for coronary artery disease may well see a significant change in the near future. The European Society of Cardiology writes, in comparing their current Barcelona meeting to their annual meeting in 2001, when the first revolutionary results of the Cypher stent showing 0% restenosis were presented:

"In the history of stent devices, Barcelona 2006 could prove as memorable as 2001."