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March 9, 2005

Trials and Tribulations
I'm going to attempt as brief a synopsis as possible of the drug-eluting stent head-to-head clinical trials that were presented on Sunday at the ACC, and comment on what I, and others, think are their implications. So while this is a longer-than-usual entry, I hope it will clarify the issues -- for those who care about these things.

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:

"You might do a different trial and find a different result. The (stents) are largely interchangeable...we've used both stents a lot."

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:

"There is no one good and one bad, one ugly and one marvelous. The reality's not there. We are in small differences and I think we need much more data to dramatically change the practice."

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:

In order to demonstrate a 100% increase in stent thrombosis from Cypher to Taxus, from 0.5% to 1.0%, more than 10,000 patients for 80% power would have been necessary...Thus, given the possibility of an alpha error in a trial underpowered for this end point, no firm conclusions regarding relative stent thrombosis rates should be drawn.

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:

"All of these trials are underpowered and unfortunately we are going to get a lot of confusion when we look at these small underpowered studies showing big differences."

Speaking of smaller studies, here are the other two: ISAR-DIABETES and SIRTAX.

ISAR-DIABETES.
The first real negative press for the Taxus stent actually came just before the REALITY trial was presented. Perhaps it initially didn't get much press coverage because it was a relatively small trial, only 250 patients -- and atypical: all diabetics. Dr. Adnan Kastrati of The Deutsches Herzzentrum in Munich, the primary investigator for the study, explained that they wanted to look only at diabetic patients who were at the highest risk for restenosis, in order to give the two drug-eluting stents a real workout -- he referred to it at a "stent stress test". His team, not funded by any drug company, by the way, thought this would be a way to "unmask" differences in the two stents because he didn't think diabetics were "different animals" -- he feels that, while the vascular disease process is accelerated in diabetics, it is not substantially different. I don't know, but it seems to me that diabetics have a number of systemic issues not shared by the population at large. But then again, I dropped out of Pre-Med right after "Quantitative Analysis".

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:

"...no patient cares about his acute gain, no patient cares about his (late) loss, the patient doesn't even care about his binary angiographic restenosis rate. He only cares if he dies, has an MI or needs a repeat revascularization procedure or has recurrent angina, etc. And that's why the most important endpoint in REALITY is the TLR rate."

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
This trial was also not funded by any company, but was supported by the University Hospital of Bern and Zurich, Switzerland. (An aside: University Hospital in Zurich is where coronary angioplasty was invented by Andreas Gruentzig; and a co-author of the SIRTAX study, Bernhard Meier, was the first angioplasty patient's physician -- see a video clip about this -- RealPlayer required.) The SIRTAX study also was not blinded (doctors knew which stent they were using) and was done at two centers, not 90 like the REALITY trial. There were over a thousand patients, however. And the patient population was, by and large, sicker and more complex than the REALITY trial. The results were not favorable to the Taxus which showed a significantly higher cardiac death rate as well as a higher TLR rate (over 50% higher than the Taxus TLR in the REALITY trial). Interestingly enough, the incidence of stent thrombosis, the big "red flag" in REALITY, was pretty much the same for Taxus, but five times higher for the Cypher. The Taxus actually had a lower thrombosis rate than the Cypher in the SIRTAX trial.

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.

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