Unraveling the Cypher Stent
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An Angioplasty.org Editorial on the FDA Warnings
About Johnson & Johnson's Drug Eluting Stent

October 30, 2003
Background
The CYPHER drug eluting stent from Johnson & Johnson / Cordis was the first drug-eluting stent to receive FDA approval for use in the United States. These devices "elute" a medication inside the artery which slows the process of inflammation, and thus reduces the reclosing of the artery, normally occurring in 25-35% of all angioplasties. Obviously, expectations were high for what was being hailed as a major advance in the treatment of heart disease. The major negative of restenosis, or recurrence, in coronary angioplasty was shown to be greatly reduced by such devices, down to single digits. Patients were understandably vitally interested in this development. Many, seeded by the advance news surrounding the CYPHER, were actually delaying their angioplasties until the device was approved, resulting in the occurrence of some unfortunate cardiac events ("Patients wait, risking heart attack", Bloomberg News, April 21, 2003).

The device was given US approval on April 24, 2003, although both it and the Taxus drug eluting stent from Boston Scientific already had been approved for use in Europe. In J&J's estimation, almost 450,000 of these stents have since been implanted in 300,000 U.S. patients (some cases require more than one stent).

Supply and Demand
The good and the bad of the FDA approval was that Cordis was now able to sell its stent, but the FDA was concerned about the shelf-life of the drug coating the stent, sirolimus. So they placed a restriction on Cordis which lowered the available supply. The FDA also restricted the stent approval to certain sizes. This created a shortfall in the supply, which upset many cardiologists ("New Drug-Coated Stents Exceeds Supply", Associated Press, June 27, 2003). Because of the overwhelming popular demand for this stent (we sat in on a number of angioplasty sessions with patients who unprompted asked the cardiologist, "So you're going to use the new medicated stent, right?") cardiologists attempted to use the CYPHER stent whenever possible.

Problems Surface
Less than two months after approval, the FDA issued a warning to physicians to be vigilant in reporting adverse reactions in the use of the CYPHER stent, since there had been a series of instances of blood clotting, including 5 deaths in CYPHER cases. ("New heart stent linked to blood clots", MSNBC News, July 8, 2003") The concern about "stretching" the sizing of the stents was raised. In a letter to physicians ("Dear Colleague Letter", Cordis, July 7, 2003) the company urged cardiologists to be careful that the stent diameter size is optimum for the artery, and not "stretched" to fit; to make sure that the stent is long enough for the length of the occluded arterial area. Correct stent sizing is crucial in proper stent placement, and variation from the optimum can sometimes give rise to complications, specifically thrombosis or re-occlusion.

Furthermore, because the point of a drug-eluting stent is to delay the inflammatory response, thus avoiding reclosure, the onset of possible thrombosis, or clotting, may also be delayed. This is why Cordis recommends administering anti-clotting medications for three months instead of the usual two weeks. Evidently, these recommendations were not being followed universally, so the FDA urged cardiologists to be vigilant in their prescription of post-stent medication.

Problems Resurface
On October 29, the FDA issued a second warning on the CYPHER stent. The numbers of blood clotting (thrombosis) and deaths had increased. Additionally there were also reports of allergic or hypersensitive reactions to the stent. So the FDA issued a warning to increase vigilance on the part of cardiologists, increase the reporting of adverse effects, and to require Cordis to do deep follow-up of 2,000 patients. According to John McB. Hodgson, MD, President of The Society for Cardiovascular Angiography and Interventions (SCAI) the subacute thrombosis rate for the CYPHER stent is extremely low, only 0.7% ("Interventional Cardiologists' Professional Society Supports FDA Advisory on Drug-Eluting Stents (DES)", SCAI, October 30, 2003). But because the drug-eluting stent is a new device, the FDA decided to exercise caution and gather more data on how and why these complications are occurring.

A Potential Panic
In our view some of the press reaction to this FDA advisory was relatively extreme. Suddenly there were headlines like "FDA Warns of Deadly Complications in Highly Touted Stent" and "Deaths prompt warning on stents". On newsgroups and in some news articles, patients were beginning to express some concern, several stating they were glad they didn't have a CYPHER stent implanted (e.g. W.D. Crotty, Fool.com, October 30, 2003).

Reality Check
The reality is that any stent has a complication rate, about 1-2% for standard bare metal stents, according to Cordis spokesperson Martin Schildhouse ("FDA issues advisory notice about SAT/hypersensitivity reactions with Cypher stent", theHeart.org, October 29. 2003 -- registered users only). There will be a certain number of thromboses, there will be some failures, complications and even deaths with any device or medical intervention. This is measured against the great number of patients who have no complications, and whose lives are enhanced by these devices. Nevertheless, a new device needs to be examined ruthlessly and "best practice" guidelines must be followed by physicians. And that is exactly what the FDA is requiring.

It is highly possible that what will emerge from the CYPHER follow-up study is a stricter post-procedure drug regimen. But much may be learned. Dr. Eric Topol, chairman of cardiovascular medicine at the Cleveland Clinic, and who is continuing to use the CYPHER stent, said he was surprised at the high number of hypersensitivity or allergic reactions reported. "This was thought to be extremely rare, if not unheard of," Dr. Topol said. " It deserves a lot of attention," ("Some Doctors to Use J&J's Cypher Stent Despite Advisory", DowJones Business News, October 30, 2003).

The FDA approval came about after extensive clinical trials were conducted in a number of centers by highly-experienced interventional cardiologists. Now that the device is interfacing with an expanded user-base and hands-on work in the cath labs, new data is being revealed. Regimens, procedures, protocols will no doubt need to be adjusted.

As for the incidence of sub-acute thrombosis in drug-eluting stents, Dr. Gregg Stone in his exclusive interview with Angioplasty.org, states, "...the rate that events were occurring were deemed initially to be excessive, but then when cooler heads prevailed, and actually scientifically tried to collect the [Cypher] data and numbers...we did in fact find that the rates were very similar to the bare metal stent thrombosis experience."

A Look Back
Angioplasty itself is less than 30 years old, and it took a decade for the procedure to gain the maturity it needed to become a major therapy in the treatment of heart disease.Andreas Gruentzig, the inventor of coronary angioplasty, always put the discovery of knowledge before any marketing or financial concerns. In fact, he refused to allow newspapers to carry the story of the first angioplasty in 1977 until he had reached a higher level of perfection with the procedure -- he knew the danger of "over-hyping" and unrealistically raising expectations, because then the early problems could hinder the progress of the procedure. We hope that the data produced by the FDA-ordered follow-up will only make the future of drug-eluting stents even more promising.

Update
On October 18, 2004, the FDA issued an update titled, FDA Public Health Web Notification: Final Update of Information for Physicians on Sub-acute Thromboses (SAT) and Hypersensitivity Reactions with Use of the Cordis CYPHER™ Sirolimus-eluting Coronary Stent . This update basically confirms the views expressed above that the rate of SAT for the Cypher is no greater than that for bare metal stents.

Update 2
As a result of the early experience with drug-eluting stents, detailed in this editorial, cardiologists realized that patient compliance with dual antiplatelet therapy, consisting of aspirin plus either clopidogrel (Plavix) or ticlopidine (Ticlid), was crucial for lowering the risk of stent thrombosis. Recommendations for a minimum of 6 months of these medications became the standard. The incidence of late or very late stent thormbosis (afer a year) is still an issue with drug-eluting stents, prompting many physicians to recommend 12 months or more of antiplatelet therapy, assuming there are no complications from the medicines, such as bleeding. Most studies have shown that total stent thrombosis is similar between bare metal and drug-eluting stents, but this percentage is still very small. See our StentCenter for the latest news and information.

We welcome your comments on this editorial.

Source: Angioplasty.org, posted October 30, 2003 -- revised October 18, 2004 and April 12, 2009)

CONTACT: Burt Cohen, Producer of Angioplasty.org

 


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