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What are some of the implications of the SAPPHIRE* trial thus far?

I think that it has shown us that certainly in patients who have co-morbid conditions, that stenting protection is equivalent or superior to endarterectomy. It has a lower risk of complications, it has a lower restenosis rate, and certainly it has a lower risk of major ipsilateral stroke and myocardial infarction. I think one point that has been discussed is the definition of high-risk that we used. The definition of high-risk is really based upon the literature, upon a variety of conditions that have been described to increase the risk of surgery, such as previous surgery on the neck or cardiac conditions. We think that’s fairly well-validated. There’s also been some discussion about including myocardial infarction (MI) as an endpoint, which, again, we feel is scientifically appropriate. All of these patients have significant generalized atherosclerotic disease, and their major cause of death is MI. They frequently do have an MI during surgery or procedures. So it makes a lot of sense to include MI as an endpoint, and all modern trials, including CREST**, are including MI as an endpoint.

There are also discussions that have taken place about the training and expertise required in order to do carotid stenting. There’s been much discussion regarding the various specialties, and differing opinions on that. I think it would help to clarify what kind of expertise it does take to perform this procedure. One very positive thing that has come out of SAPPHIRE is that many specialties are now working together in carotid stenting. There’s close cooperation between cardiology and vascular surgery and vascular medicine in this regard. Multiple training programs have been set up. One very important point is that carotid artery stenting is probably the most scrutinized and carefully researched interventional procedure that we have ever had. The rollout of this procedure is really the most careful that I have ever seen, with the most extensive training programs created by all the companies and which the FDA has mandated.

Dr. Ted Feldman of Evanston Northwestern, during a presentation on the PressureWire at the 2004 SCA&I, said: “We do not know anything about the meaning of gradients in a carotid circulation. People argue about how to measure carotid stenoses. Nobody has tried physiologically to quantitate them.” Can you comment?

I think it’s a good point. We have actually used the PressureWire in the carotid. The difficulty simply is that in the carotid you really don’t want to instrument it unless you have to and you’re going to fix it. Compared to the coronaries, people are a little more reluctant to put a wire in the carotid. For that reason, I think there is limited desire, because of the risk of stroke, which is low, but does exist. Also, we just don’t have the literature base for that as yet — somebody has to create that. Generally, since noninvasive technology like ultrasound is so good, by the time you get to angiography, the decision has generally been made to do an intervention. Of course, the majority of people are not going into angiography from ultrasound, they are going into surgery. There is no opportunity to do a hemodynamic measurement. We have done some IVUS and some PressureWire measurement in some very complex cases, particularly with fibromuscular dysplasia, where it is sometimes very hard to discern how severe the stenosis is. We’ve found it to be helpful. In routine atherosclerotic stenosis, I can generally get a pretty good idea of lesion severity between the ultrasound and the angiography.

What are your thoughts on use of CT or MRA?

I really favor ultrasound. I have found that MRA is not as accurate as ultrasound. It often overestimates the degree of stenosis. It is a more expensive test, and some patients are claustrophobic, and scheduling is more difficult. CT has contrast, and I think the contrast is a major issue. Some of these patients have renal insufficiency. You’re giving a large dose of contrast, and after that, if you go to stenting, you'll get another dose of contrast in short order. So I really do favor ultrasound. I think a well-validated ultrasound is the most accurate diagnostic tool that we have for carotid artery disease.

At the Cleveland Clinic, we always do the ultrasound here. We do find some discrepancy between ultrasounds done in offices or small hospitals and our ultrasound. Before we make a therapeutic decision, we always like to confirm with our own ultrasound here, in order to validate it. I think in general, the ultrasound is a benign test, and it is helpful to get it at your own institution before you enroll the patient into a carotid stenting study or proceed with carotid stenting.

How is the brain affected post-stenting versus post-endarterectomy?

We know from SAPPHIRE that the brain suffers less major ipsilateral strokes after stenting compared to endarterectomy. We did have neuropsychological testing performed in the CAVATAS*** study, and there were no differences in the neuropsychological testing between the angioplasty patients and the endarterectomy patients. Remember in CAVATAS, there was no emboli protection used. I think with these two major randomized trials, stenting with emboli protection is at least as neuroprotective as endarterectomy, and I suspect it is more neuroprotective.

What are some of the clinical studies going on at present?

I think there are several very important studies going on. CAVATAS 2 is very important, and CREST is important. There will be some large, low-risk, randomized and case-controlled studies starting in the U.S. in 2005, which will be very important also. We really are living in the golden age of carotid artery research and we will have a lot of data in the next few years.

How long do you feel it will be before there is a high number of physicians in the U.S. comfortable and experienced in performing CAS?

I think by early 2006 or 2007, we will have a decent number of physicians.

What you feel is the most important part of the CAS learning process for physicians? Many people have said that simply making the decision of whether or not to treat the patient is crucial.
I agree, that is always the most important decision in any clinical scenario. Making the decision whether to treat or not, ie, clinical judgement, is definitely the most important thing. I think managing the patient, both before and after the procedure, is also very important. From a technical perspective, access remains the most challenging portion. We are working on simplifying that, and actually it's simpler than it used to be.

What’s the current status of the Angioguard device and Precise stent?

That particular device has not yet been commercially launched as yet. There is a post-surveillance registry going on with the Guidant device that's just starting up.

Your October 2004 New England Journal of Medicine article noted that “A larger sample might have provided more support for the secondary finding of the superiority of stenting.” Do you expect that finding in the high-risk symptomatic patients to be confirmed as future studies go forward?

I think there would be a high probability of that. If you look at SAPPHIRE, the treated patients, we actually did show superiority. In the intention to treat analysis, it was not inferior. And unfortunately, that study was designed basically as a non-inferiority study. I don’t think anybody realistically had expected stenting to do so well compared to surgery. I think everyone underestimated the true complication rate for surgery.

What about the procedure itself do you feel leads to its success?

I think people underestimate the stress to the patient of having surgery. They underestimate the impact of carotid occlusion for 15 minutes and they’re assuming that ischemia has no impact, and that only embolization has impact. I think that hypothesis is perhaps not correct. If you look at some brain biomarker studies, they clearly demonstrate a increase of release of these markers during carotid occlusion in surgery. I think it’s interesting research that probably needs to be pursued more, but it probably will not get pursued more, since endarterectomy will be performed less and less. With stenting, we really solved the Achilles’ heel, which was embolization. Once you take out embolization, which emboli protection devices are fairly effective at doing, the rest of the procedure is very elegant and very patient-friendly. The other factor is that the carotid artery, from a restenosis perspective, is actually the most forgiving artery in the body. It does not restenose. I think this may be because it is so large and perhaps the geometry. It’s the only place where you can perform endarterectomy. You can’t perform endarterectomy in the coronaries because the restenosis rates are too high — you have to do bypass. I think it is just a forgiving artery in terms of restenosis. The restenosis rates in SAPPHIRE were actually less for stenting than for surgery.

What is the plan for looking at asymptomatic patients?

One of our major areas of interest going forward is to look at vulnerable plaque and asymptomatic patients, and try and predict what asymptomatic patients are at risk of future stroke, as well as try to be more precise in which patients get treated. Right now, we don’t really have a very specific way of doing that. It is based only on the degree of stenosis. That probably is one of the poorer predictors of your risk of stroke, if the coronary arteries are any indication.
In terms of the lower-risk studies coming up, they will include both asymptomatic and symptomatic patients. Most of the patients I am sure will be asymptomatic, given the distribution of what has been seen in previous carotid studies. These studies will be similar to SAPPHIRE except these patients will not have co-morbid conditions. Symptomatic patients will be at 50% stenosis, and asymptomatic patients will be at either 60% or 80% stenosis, depending on the study. There are multiple studies being planned.

Dr. Yadav can be contacted at yadavj@ccf.org

*SAPPHIRE: Stenting and Angioplasty with Protection in Patients at HIgh Risk for Endarterectomy
**CREST: Carotid Revascularization Endarterectomy versus Stent Trial
***CAVATAS: Carotid and Vertebral Artery Transluminal Angioplasty Study