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December 2006 Archives:

December 12 The FDA Stent Panel: A Catalytic Converter
Initial impressions of last week's FDA panel on late stent thrombosis

December 28, 2006 -- 10:30pm ET

DES'ed and Confused: What the FDA Stent Safety Panel Means for Patients
If you had been worrying about that drug-eluting stent (DES) implanted in your coronary artery, your concerns were no doubt greatly reduced by the extensive news coverage following the much-anticipated FDA stent safety panel held on December 7-8. Here's a small sample:

Drug-Coated Stents Don't Boost Death Risk, U.S. Advisers Say (HealthDay)

Panel says wide use of drug-coated stents risky (Reuters)

Panel: Drug-Coated Stents Are Safe (CBS / AP)

Panel Urges Caution on Coated Stents (New York Times)

Drug-Eluting Stents Do Not Increase Risk of Heart Attack or Death, Benefits Outweigh Increased Blood Clot Risk, FDA Advisory Panel States (Kaiser Network)

FDA Advisory Panel Recommends More Warnings About Drug-Eluting Stents (Kaiser Network - 3 days later)

Confused? Of course you are. And if you are the recipient of a drug-eluting stent, you're probably confused and scared -- because the stakes are high, and this device can't be taken out!

So, let's take a breath of fresh air: inhale...and now slowly exhale.

The clinical trials for both the Taxus (Boston Scientific) and the Cypher (Cordis / Johnson & Johnson) drug-eluting stents were done in simple uncomplicated patients: those with a previously untreated ("de novo") blockage in a single vessel in a straight-forward location. The stents were approved by the FDA for those situations, because they showed a clear and significant benefit over bare metal stents: much lower chance of reblockage.

In order to get their devices approved, companies tend to design their clinical trials for this straight-forward type of patient population (one that will show a clear benefit). But in the "real world", almost two-thirds of the time, interventional cardiologists use these devices outside of these strict and limiting definitions. There is nothing illegal about this.

Physicians have studied these additional uses and shared this data with other doctors at the major heart meetings. They use these devices in many "off-label" indications (multiple stents, multiple vessels, in-stent restenosis) because they feel that the patient is better served by the newer device that shows less restenosis. More restenosis means more repeat procedures and more complications; studies have shown that restenosis is not benign -- it increases the incidence of heart attack and hospitalization. Furthermore, prior to drug-eluting stents, physicians often used bare metal stents in these same off-label indications -- they did not perform as well as drug-eluting stents do.

But over the past year, concerns about the tendency of drug-eluting stent patients to experience stent thrombosis (not a reblockage, per se, but an acute gathering of platelets, a.k.a. a blood clot) six months or more after implantation has prompted a new look at the use of these devices. The incidence seems very small, but the data about this population, as evidenced at the FDA hearing, are incomplete, not very robust, in the words of one panelist to me, "We've got lots of data -- it's just that it's lousy data!"

The FDA panel clearly stated that, when used within the confines of the approved uses of the original clinical trial population, there is no increased risk with drug-eluting stents -- and there is a considerable benefit: freedom from restenosis.

But the data for "off-label" uses is not clear: these are more complex blockages, in sicker patients, with more Plavix and aspirin -- in the words of panelist Dr. Eric Topol, there are "a lot of moving parts -- it's a big grey area, and the risk may be considerable".

And there lies the problem with "off-label" use -- it's not that this use is dangerous; it's that the FDA doesn't regulate "off-label" use and therefore doesn't require long-term studies of patients in these situations before approval. So the data is not so clear. The FDA did require Cordis to do a followup post-market study after approval of the Cypher stent in 2003. But Cordis stopped collecting data after one year, and they were taken to task by the panel chairman Dr. William Maisel for not following up longer. However, the FDA agreed with Cordis that they only requested a one-year follow-up -- and added that in retrospect, it should have been longer, and probably will be for future devices.

As to how this affects patients, we wrote a "Patient Advisory" right after the European Congress of Cardiology four months ago, and nothing discussed at the FDA panel has changed what's in that Advisory. Most cardiologists have been recommending longer-term Plavix and aspirin for quite a while now. I suggest patients with questions read that Advisory and discuss it with your doctor. For many patients drug-eluting stents work great; for some not necessarily, especially those who have a risk of bleeding, making long-term Plavix therapy not a good option.

What has changed this month is something I discussed in my last entry: two days of panel discussions by the FDA have given these problems a public airing, providing instant and widespread "patient education". The message was that there is something to be concerned about after all. And this message prompted an all-out defense by the two drug-eluting stent manufacturers: Boston Scientific immediately ran full-page ads in all the major U.S. newspapers, Cordis issued press releases about "educational programs", and both manufacturers mass-emailed the professional cardiology community with copies of the PowerPoint presentations they made to the FDA.

And, of course, their stocks went down a bit as analysts saw the extremely lucrative market for drug-eluting stents begin to shrink. Can you say "a 20% reduction in a $6 billion annual market equals $1.2 billion"?

However, all's good now....

Today's New York Times announced, "Street Expresses New Confidence in Drug-Coated Stents". The "Street", of course, is not the one you live on, but where stock analysts dwell, and where they now are feeling optimistic that drug-coated devices will still account for 75-80% of the stent market.

What does this mean for patients? Well, the article is not in the Health section, but in the Business section. Interestingly enough, the article ends with:

It seems farfetched that drug-coated stents could fall that far [to 40%]. Unless, of course, there is more bad news about clotting risks.

Perhaps not so farfetched if patients who are about to have an intervention and have read the news today oboy and don't particularly want to risk a stent thrombosis in two years and don't like the idea of taking Plavix for a year or two or life, if those patients spend a few extra minutes in their cardiologist's office discussing this, and their cardiologist determines that maybe after all this patient is at low risk for restenosis, or won't be compliant with the Plavix/aspirin combo, so why not just go with a bare metal stent. Maybe that might have an effect on "the Street".

After all, at its worst, the restenosis rate with bare metal stents was 20%. The closer cardiologists come to predicting who that 20% might be, the less important the drug-coated stent will become. Dr. John Spertus of the Mid-America Heart Institute in Kansas City told me a few weeks ago that probably 60% of patients would benefit from drug-eluting stents. Dr. Sanjay Kaul of Cedars-Sinai in L.A. thinks it's more like 40%.

We welcome your opinion. After all, when the data are lacking, your guess is as good as anyone's.

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December 12, 2006 -- 2:45pm EDT

The FDA Stent Panel: A Catalytic Converter
I'm reflecting on last week's FDA panel, convened to discuss the issue of drug-eluting stent safety and late stent thrombosis. I plan to write over the next couple days about what happened there, but the important thing is that something DID happen there.

There were over 25 presentations given by industry representatives, cardiologists, surgeons, the three major professional cardiology groups, me and a patient who visits our Forum -- and for two days from 8:00am on, the panelists listened and asked questions, sometimes probing, sometimes challenging, and they debated among themselves whether to recommend that the FDA attach stronger warnings, change the labels, lengthen the recommended duration of Plavix or Ticlid and aspirin.

Even though the panel wound up disagreeing on several key issues and did not recommend many of the label changes that they might have (indeed, it is ultimately the FDA's decision as to what to do officially; the panel is only advisory) the bottom line is that these issues, which are complicated and unfortunately not easy to judge due to lack of sufficient and "good" data, these issues were aired in public, in a room of 500, many of whom were reporters, seated against the walls, close to power outlets, tapping away non-stop on their laptops and condensing the proceedings into stories instantly filed with the home office.

Regardless of the final recommendations, the current state of knowledge about these devices, the pluses and minuses, saw the light of day -- actually two days. And as they went on, one heard the constant refrain of the panel -- how does this translate into clinical benefit for our patients? I've observed lots of professional meetings where interventionalists debate p-values, relative risk assessment, which device is better, etc. But here you had a broader spectrum of active participants: clinical cardiologists, surgeons, statisticians, regulators, me, and The Patient (who truly moved the meeting with his story and plea for more support).

The FDA may or may not take any regulatory action right now. But the real action was the meeting itself. The cats were all let out of their bags. This time the FDA used its power as a catalyst: something that enables a reaction without becoming part of it. And that reaction, both professional and private, will certainly result in some self-imposed limitations on use of these devices in certain patients, because physicians will be weighing the risk/benefit more -- even though the risk is very very low (I'll be talking more about this later).

Hopefully what will happen is that, given more appropriate patient selection and compliance strategies (more on this later, as well), patients who are best served by drug-eluting stents, and there are many, will get them with confidence, and that those who may not do as well, won't.

The FDA has come under much criticism in recent days, some from yours truly. There is no question that the agency needs to profoundly improve post-market monitoring and clarify for the public the meaning of "off-label" use of drugs and devices. But this event was impressive in its scope -- and the ability for the public to speak and influence decisions in a very direct way was not unlike some Board meetings I have attended in the little village where I live. My thoughts were echoed by Daniel G. Schultz, MD, the Director of FDA's Center for Devices and Radiological Health, who concluded the panel:

"This meeting needed to happen... In the past I think sometimes we shied away from bringing these kinds of controversial issues. But to me what these last two days have demonstrated is that this is the best way, maybe the only way, to get some moving forward, if not resolution, of this kind of complicated issue."

In coming posts, I'll be exploring some of the technical issues and specific concerns about these devices, the media reporting of the meeting, and the post-panel ad campaign to win the (yes) hearts and minds of patients and physicians.

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