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March 2005 Archives
Quickies At the other end of the spectrum is a study from Northwestern University published in today's JAMA (Journal of the American Medical Association) titled "Diabetes and Coronary Revascularization". This review of clinical trials from 1995-2004 states that percutaneous interventions aren't as good as surgery for revascularizing diabetic patients but the conclusion is:
In other words, the landscape is totally changed with the advent of drug-eluting stents and newer anti-platelet drugs, so the outcomes of earlier trials are basically irrelevant. This is a problem I discussed back in October, that so much of the so-called information, especially on the internet, about stents and angioplasty was written pre-drug-eluting-stent-era and is therefore not really relevant. Finally, in a related story, as reported on theHeart.org, the European Society of Cardiology has issued practice guidelines for PCI (percutaneous coronary interventions) which are a bit different from their U.S. counterpart. Once again, the rate of change in medical practice often outpaces the official guidelines. They write:
The U.S. guidelines do not even mention drug-eluting stents -- as I have written, it's not just that drug-eluting stents have improved outcomes; they have radically improved outcomes to the extent that management of patients with coronary artery disease is changing from what is was only two years ago. (You can read the ESC guidelines here in PDF format -- 44 pages)
Trials and Tribulations I also want to point out what has become an all-too-prevalent pattern in health care reportage -- initial reports on healthcare issues more often than not are made by business reporters: the USA Today articles from Tuesday are the DowJones headlines from Monday which are interpretations of the scientific presentations from Sunday. To some extent, it's like the game of telephone we played in fourth grade: the data get slightly changed on each iteration. And so it went with the "Stent Wars" reports, as I described in my last post -- the first blush was that the much-anticipated REALITY trial was a draw, so positive headlines touted the "there's no difference" story. Then, when reporters hooked into the marketing buzz from two other smaller and less-anticipated head-to-head trials, the tide turned and within 24 hours we went from Reuters' "J&J Stent Study Falls Short" to Forbes' "J&J Stent 'Gaining Some Real Momentum'" to Tuesday's USA Today declaration that "Studies of Rival Stents Suggest That One is Better". Contrast that perception with former ACC President and angioplasty pioneer Dr. Spencer King's comment that he is far from convinced there is any problem with the Taxus stent -- he stated:
Of course, I read this in the Wall Street Journal. So, bottom line, is one stent better than the other? I say "No!" But what do I know? I'm not a doctor -- I just play one on the Internet. Here's my point: there just is not enough data to show that one stent is "better". And that's not just my opinion but also that of Dr. Marie-Claude Morice who ran the REALITY trial (funded by Johnson & Johnson). In her words:
Speaking of the REALITY trial, much has been made of the significantly higher thrombosis (blood-clotting) rate seen in the Taxus. Most studies to date have shown all stents, bare metal, Cypher and Taxus, to have thrombosis rates somewhere under 1%. But in REALITY, the Cypher scored low at 0.4% and the Taxus was more than four times higher at 1.8%. J&J touted this outcome in their press release, "REALITY Trial Data Suggest Drug-Eluting Stents Differ Significantly in Rate of Blood Clot Formation-Stent Thrombosis" and this story has been echoed by the retail press. Remember, the REALITY trial included 1,353 patients, so the above percentages translate to thrombosis in 3 Cypher patients and 12 Taxus patients. But, here's the rest of that story. This "significant difference" has to do with one single patient. Turns out one of the patients had actually been randomized for Cypher, but his/her anatomy was too tortuous and the cardiologist couldn't deliver the Cypher to the lesion, so they switched to the Taxus stent, which they were able to deliver ("deliverability" is a characteristic that Boston Scientific has touted as one of Taxus' advantages). Unfortunately, the patient developed blood-clotting, which Dr. John Lasala of Washington University in St. Louis said might have happened with the Cypher as well, since "the anatomy was complex". So if the Cypher had been delivered, as was planned, and it thrombosed, the percentages would have changed to 1.6% vs. 0.6%, bringing the difference into the statistical realm labeled "not significant" -- so leave that adverb "significantly" out of the press release headline, please. As Dr. Eberhard Grube of Siegberg, Germany, the official "discussant" on the REALITY study, said to the audience at the ACC:
Moreover, late stent thrombosis data, beyond 30 days, was not reported. Dr. Grube said "I would have liked to have seen the 8-month results". Ironic, isn't it, that one of the Taxus stent's perceived advantages caused it to get a worse score on thrombosis. Now, none of this is to say that the data should be ignored. Stent thrombosis is an extremely serious event and Boston Scientific states that it is taking it seriously. The question is just whether the data is saying "there's something wrong with this device" or not. The same fears were at the forefront back in the fall of 2003 concerning the Cypher stent -- the conclusion by all, including the FDA, was that the incidence of stent thrombosis there was no greater than that for bare metal stents. The same may be true here. The problem is summed up best by Dr. Gregg Stone:
Speaking of smaller studies, here are the other two: ISAR-DIABETES and SIRTAX. ISAR-DIABETES. The primary end point of the study was Late Lumen Loss (LLL) which is the amount that the lumen (open channel of the artery) has closed between the immediate post-stenting measurement and the measurement at the 9-month angiographic follow up. Anyway, the Cypher definitely scored better on that. This was no surprise because in every study done to date, in many thousands of patients, the Cypher stent has shown less Late Lumen Loss than the Taxus. The question is what does that mean for the patient? A secondary end point was binary angiographic restenosis. If the artery treated showed a reblockage of 50% or more at 9 months, it has officially restenosed. On this, the Cypher again did almost 2 1/2 times better, showing a 6.9% restenosis, as opposed to the Taxus at 16.5%. But then, there's the other secondary end point, TLR -- Total Lesion Revascularization -- did the lesion (blockage) need to be reopened? Even if there was restenosis, did it cause symptoms or clinical events that required a repeat procedure or bypass surgery? In this measure, although the Taxus was higher (12.2% to Cypher's 6.4%) it was not considered significant statistically due to the small numbers in the trial. So what measures are important? Here's Gregg Stone again, speaking about the REALITY trial:
His point is that the TLR (do you need a repeat procedure?) rate is what's important, and in ISAR DIABETES, the difference in TLR rates was statistically insignificant -- and the MI and death rates for both stents were similar. Another interesting factoid is that the number of diabetic patients enrolled in the REALITY trial was 378, 50% more diabetics than were in the ISAR-DIABETES trial, yet the REALITY trial showed virtually no differences in outcomes (the TLRs in REALITY were 5.4% for Taxus to 5.0% for Cypher). Go figure. SIRTAX Which brings me to the point of this all, that I truly think Gregg Stone's comment is correct. We're all getting confused by inconsistent results from these various "underpowered" trials. Which is not to diminish any of the data. Any anomaly that surfaces should be investigated. But on the flip side, even the largest clinical trials can completely miss what turns out to be a significant issue. Cardiologists have not thought that stent allergies were a big deal. Yet for years, we've gotten patients writing into a Forum Topic on Angioplasty.Org that they've had terrible allergic reactions. Allergies were never reported as a major concern during the clinical trials for the Cypher, yet at this week's ACC, researchers at Emory University report that almost 2% of patients who received a Cypher stent in the fall of 2003 had allergic reactions to it, leading to an increased incidence of revascularization or heart attack. So watch the data, definitely try to figure out what is causing certain events, but also be aware of the science of statistics in terms of judging whether one therapy is "better" than another. And be aware that there is a lot of money involved in these "Stent Wars", so there is a lot of marketing going on. And, by way of full disclosure, our web site Angioplasty.Org does receive funding from Boston Scientific, manufacturer of the Taxus stent, although we are an independent educational site.
I Told You So. What's That You Say? Oh...Really?
Never Mind...
A few days later, the COO of Boston Scientific said that he had information from physicians who were part of the REALITY study, and he predicted there would be little difference found between the two stents. And on Sunday, after those predictions became REALITY, both Drs. Marie-Claude Morice and Gregg Stone (investigators for the J&J REALITY and TAXUS V trials respectively) agreed on one thing. In the words of Gregg Stone:
Like I said. But this was just the REALITY trial. Two other presentations on Sunday also compared the two stents, ISAR-DIABETES, which looked only at diabetic patients, and SIRTAX, which stands for SIR-olimus vs. TAXus but it sounds like money to me. And money it was. The results of both these trials were not-so-good for the Taxus stents, and the "No-Difference-in-Stents-REALITY-Failed-To-Show-One" headlines in the press began to change to things like "One Stent Better Than the Other" and "Johnson & Johnson Stent Gaining Momentum". He's up, he's down, he's up again! Whatta fight, folks, whatta fight! It was like the running gag on the original Saturday Night Live, when news commentator Emily Latella (played by Gilda Radner) would vociferously put forth her opinion until interrupted by Jane Curtin with some basic information that proved her totally wrong and after a short pause, Gilda would turn to the camera, with a sheepish smile, and say, "Never Mind!" I'll discuss the results from all the Sunday presentations in my next entry.
REALITY Check Yes, as I promised, the results of this heart-to-heart study show that both stents work very well indeed -- and that the rival companies of Boston Scientific and Johnson & Johnson/Cordis are both going to have to spin the results a bit if they are going to portray their product as superior. Well actually I take that back. J&J already spun the results for Boston Scientific by defining the primary goal of the REALITY trial, which they sponsored and paid for, as showing the superiority of the Cypher Sirolimus Drug-Eluting Stent over BSC's Taxus Paclitaxel Drug-Eluting Stent -- a very risky goal which, when it didn't pan out, allowed BSC's Chief Operating Officer Paul LaViolette (and others) to say, and correctly so, that the REALITY trial failed because it didn't show superiority. The phones must be buzzing between New Jersey (J&J HQ) and Florida (home of Cordis and the ACC, where everybody is right now). A brief but interesting side-note: J&J's press release, which doesn't mention that the two stents were equivalent in restenosis prevention (the primary endpoint of the study) until paragraph four, also has a trademark disclaimer at the end of the release which states, "Taxus is a trademark of SciMed Life Systems, Inc." -- it's almost as if they can't bring themselves to say the words...Boston...Scientific.... (BSC acquired SciMed a decade ago.) Okay. Enough about the fact that they're both good. What are the differences? What about the reported increase in SAT rate for the Taxus and the other findings? And what about the positive results from the TAXUS V study of small, large and long lesions with multiple stents and from J&J's ARTS II study of multiple stents in multivessel disease? And then there's the ISAR-DIABETES study from Deutsches Herzzentrum, Germany which showed Cypher to be better than Taxus for treating diabetics. Bottom line: what does this data mean for patients, the people who will be walking around with these metallic sleeves in their hearts? More tomorrow.
REALITY Additionally, Boston Scientific's TAXUS V trial, in which difficult-to-treat cases were studied, met its primary goals, showed the TAXUS to be effective in reducing restenosis in this patient population, and made the company very happy, as indicated in their press release, although the actual rates were a bit higher "than analysts expected". I'll be commenting more on this later as well, especially on what cardiologists, as opposed to analysts, expected.
The Hype Gets Hype-ier
And while I'll be reporting the results as they come in over the next few days, I can't help but think back to the early days of angioplasty when two different companies also were duking it out, but over balloons. They were USCI and ACS. USCI, which introduced coronary angioplasty to the U.S., subsequently kind of disappeared, was purchased by Simon Stertzer's AVE and then delivered to Medtronic when that acquisition occurred. ACS, a John Simpson company, became the interventional division of Guidant, now headed at warp speed to merge into the J&J mothership. USCI had their Gruentzig balloon which measured proximal and distal blood pressures on either end of a blockage to determine "when the procedure was done" -- a small gradient, or difference between the two pressures, signified that the blockage had been successfully dilated. ACS, feeling that the X-ray fluoroscopy the doctor saw in the cath lab was a good enough measure, scrapped the pressure measurement in order to make a significantly thinner and lower-profile balloon which could get into narrower vessels and track around more tortuous curves in the coronary anatomy. And each company marketed its product as better than the competition's: "use ours -- it's safe and effective"; "use ours -- it's safe too, but easier to use." The big difference is that back then the field of angioplasty was still fighting for recognition as a viable treatment alternative to bypass surgery. Even Andreas Gruentzig originally thought maybe only 5% of patients would be helped by his invention (it's well over 50% today and drug-eluting stents may push that far higher). And there was far less money involved. But even so, the sales forces of the two competing companies still acted just like football teams, trying to out-maneuver the other. The companies sponsored events, cocktail parties, demonstration courses, cocktail parties, instructional materials, all to keep their name and product in front of the cardiology community. They even had their own "stables" of endorsing cardiologists. Gruentzig, Myler, and Stertzer were seen as "USCI docs"; Simpson and Hartzler were ACS, and so on. But I think the doctors themselves were not so black-and-white about it. Geoff Hartzler told me not long ago that even though the companies set up this competition between cardiologists, he always had great respect for Gruentzig and vice-versa. In the early days the challenge was making the procedure succeed. And as it did, the marketing grew, the money grew, and now we are looking at a $5 billion/year market just for drug-eluting stents. So in advance of Sunday's REALITY and TAXUS V presentations, our e-mailbox here has been peppered with press releases, flash presentations and analyst webcast invitations -- and, yes, invitations to cocktail parties in Orlando. And, as I've written, there will be differences in the results between the drug-eluting stents, but they won't be anywhere near as significant as the differences between any of them and the previous device of choice, the bare-metal stent. Check back over the next few days -- I'll be trying to keep up with the flood of ACC info. |
Personally,
I still like my original description of this competition as "Stent
Wars" -- a term I coined a few years back for