View From the Cath Lab: Hot Issues in Cardiology

Three leading interventional cardiologists provide international perspectives on the most important issues confronting their specialty and how they will impact the device industry.

Three leading interventional cardiologists from around the world provide international perspectives on the most important issues confronting their specialty and how they will impact the device industry.

By Stephen Levin

At this year's JIM (Joint Interventional Meeting), one of Europe's leading interventional cardiology conferences held annually in Rome, IN VIVO convened a group of three leading interventional cardiologists to provide a global perspective on the critical issues facing what continues to be perhaps the most aggressive and rapidly evolving of all clinical specialties. The physicians interviewed were: Peter J. Fitzgerald, MD, PhD, Stanford University School of Medicine ; Eberhard Grube, MD, Siegburg Heart Center (Siegburg, Germany); and Gregg W. Stone, MD, Columbia University Medical Center and the Cardiovascular Research Foundation (CRF, sponsor of the Transcatheter Cardiovascular Therapeutics [TCT] conference, which is the leading interventional cardiology conference).

Interventional cardiologists are among the fastest adopters of innovative medical device technology and among the clinicians who work most closely with the device industry. This pattern continues as these physicians expand their practices beyond the coronary vasculature and into peripheral artery disease (PAD), carotid stenting, valve repair and replacement, and treatment of structural heart defects such as PFOs. The three physicians interviewed are among the most experienced in the world, not only clinically, but also in terms of dealing with medical device companies, particularly start-ups in developing innovative new products. In this discussion, they provide a candid, state-of-the-state perspective on the issues confronting the specialty and their impact on the medical device industry.

IN VIVO: Can you start by explaining the focus and intent of the JIM conference?

Eberhard Grube, MD: I think it's very important to have a cardiologists' meeting that is international in scope and at the same time intimate enough for physicians to interact with other physicians. One of the criticisms that we hear about the very big meetings is that people have to worry too much about concurrent sessions, the venue is very big, the hotels are very big and it's hard to spend time with your colleagues. Obviously, we're not trying to compete with the big meetings, so we

try to focus on three things. The first is live case transmissions from a maximum of three or four sites. Second, we want to keep the meeting to a manageable size so people have a chance to communicate with each other, to look at the live cases, and to then choose the particular sessions that interest them. And third, we're trying to show new devices and technologies, but at the same time, when we perform the live cases, we are also looking to show what is proven to be effective in everyday practice.

How do you strike the balance between showing interventionalists what they can do tomorrow in their cath labs, while also informing them about technologies that may not be available for several years, if at all, such as the discussions about angiogenesis and vulnerable plaque?

Peter Fitzgerald, MD: Physicians who are going to embrace technology today need to understand where that technology is going to be tomorrow and how best to apply it to certain situations. We've seen the landscape in terms of clinical scenarios in the cath lab change drastically in just the last three years. We're looking at coronary artery disease completely differently now than we did in 1996 and 1997 and that means, as clinicians, we have to know about some of the technologies on the horizon because, believe it or not, they'll be here quicker than we think. The interventional cardiologist will be a vascular specialist as time goes on, embracing not only technologies inside the coronary arteries, but inside the heart and outside into the peripheral vascular area as well. So I think it's important to have that mix of what's here today, but also what's coming tomorrow.

And the feedback we get from physicians is that they appreciate getting both perspectives. There are those who are more interested in new technologies, and there are others who prefer having that practical, "What am I going to do today?" viewpoint. As Eberhard said, this conference caters to that mixture, which is very important because technology without a bellweather of applicability is not worth pursuing. And that interaction is fostered at this meeting.

As you noted, one of the strengths of this meeting is its focus on new technologies. One of the most significant areas of innovation within interventional cardiology is imaging modalities, from the changes in the use of intravascular ultrasound (IVUS) in the era of drug-eluting stents (DES) to multi-slice CT scanning, which was also on this year's program. Peter, imaging is an area you've long been involved with, talk about the changes taking place in interventional imaging technology.

Fitzgerald: I think that's a very important area, and we saw some cases at the conference from Siegburg that showed us the tip of the iceberg of where imaging is going and the role it will play as we embrace these new technologies. But we also know what we need to develop imaging technology even further and that is additional guidance. We can't just bring in technologies that have a third and fourth dimension when in fact we're looking at those images with the same fluoroscopic modalities that we had ten years ago. The CT, the multi-slice CT, and MR are going to play significant roles in the diagnosis and following of coronary disease in the next five years. We will not be doing diagnostic caths five years from now in the standard catheterization laboratory. Coronary disease will be diagnosed in facilities outside the lab and as a result we'll do many more interventions. But the whole landscape of diagnosis and how those patients are followed will radically change in the next five years.

Diagnostic angiography has always been a major part of an interventionalist's armamentarium. Where do you see those diagnostic imaging procedures being performed in the future?

Fitzgerald: They will be performed further back in the process from the therapeutic intervention to start out with because the information structure is really difficult to change so it will be hard to have magnets and some of the other imaging capabilities required for those advanced technologies integrated into our capital equipment quickly. From a diagnostic standpoint, the imaging will occur early and it will be performed at centers outside of the cath lab, with subsequent referrals for particular interventions. Eventually those two will combine and then there will be a true integration of the diagnostic and the therapeutic under one imaging scan. But that's going to take time.

As you talk about the changes that will occur in cardiovascular imaging, I'm struck by the fact that, traditionally, start-up companies have been the lifeblood of new interventional technology development. But historically that has not been the case in imaging technology, which has largely been the province of major capital equipment companies. Is there a role for diagnostic imaging start-ups?

Fitzgerald: I'm probably not a good one to comment on that because, along with my partner, Paul Yock, I've fallen into just about every pothole imaginable in launching catheter-based diagnostics start-ups over the past 15 years. But with that in mind, we saw technology yesterday beautifully used in a cath lab that has been pioneered by small companies, which is OCT (optical coherence tomography). Ten years ago, interventionalists would have loved to have had an eyeball on a guidewire. Now we are actually getting imaging on a guidewire and it opens up the whole spectrum of possible therapies that can be tailored to plaque-specific milieus. Developing miniaturized imaging technology and combining that with therapeutic applications can also help with reimbursement because traditionally there's been no problem getting reimbursed for the therapy but the question has always been how to get paid for the diagnosis. If you combine the two, you could wind up with a better focused and guided therapy with this miniaturized imaging modality that could be better reimbursed. So the combination, I think, is going to break open some of these small therapeutic technologies with the aid of OCT technology.

Grube: This raises the whole question of the role of small companies in device development, generally speaking. The role of the small companies really is to brainstorm what's needed because they can adjust very quickly to changes while big companies are better at incorporating new technology into the market. The advantage of the small start-ups is that technologies such as the OCT forward-looking visualization capability will never be developed by the big companies. This will be developed by smart engineers coming from small cap companies. Then once they've proven the value, the big companies will integrate that technology into the market. I think there will continue to be a huge role for small start-ups. We did some live CTO (chronic total occlusion) cases at the conference that showed how advanced imaging helped improve our techniques in those cases. Now that we are getting better at CTOs, and as the technique and the technologies improve to become more widely applicable so that a larger number of physicians can perform these cases, there will be new challenges for technology in other areas. That means there will always be a huge role for small companies.

Interventional cardiology is the clinical specialty that has most heavily relied on evidence-based medicine, using randomized clinical trials frequently to assess the clinical value of new technology. All of you work a great deal with small device companies, who have been responsible for much of the interventional technology innovation. As the cost of clinical trials continues to increase, what burden does evidence-based medicine place on small companies? How critical is evidence-based medicine to technology development, given the criticism that clinical trials don't reflect real-world patient experience?

Gregg Stone, MD: Evidence-based medicine is important because it's increasingly playing a role in the decision-making process for device utilization. Because of the cost pressures that we're all under, we are seeing increasing pressure not to use expensive technology unless there's an evidence base to show that it's safe and effective. There have also been many therapies that people have adopted that have either not been effective or actually not been safe. So I think we're going to continue to be on the bandwagon saying that new therapies in particular should not be widely adopted until they are proven safe and effective. That being said, evidence-based medicine is not the only factor influencing utilization decisions because we are in a resource-constrained time and the reason, for example, that distal protection devices are not being adopted widely in Europe despite the widespread evidence of their efficacy from several large randomized trials is because of cost. Another example is intravascular ultrasound, which is very poorly adopted in Europe but has reached 40–50% penetration in Japan. What's the difference? There are many, but one of the major differences is that IVUS is reimbursed very well in Japan. That produces a financial reason why physicians could get comfortable with the technology and develop the expertise; in this case, I think that the Japanese use IVUS extraordinarily effectively precisely because they had that financial constraint removed.

I know that evidence-based medicine does place an extra burden on start-ups, but appropriately so. Start-ups introduce tremendous new innovative technologies, but they are also technologies that can potentially do harm. So I think start-ups should have a burden to have to prove the safety and efficacy of their products. I think devices, especially with what you see happening to drug eluting stents, have now entered into the realm where you get almost pharma-type returns on your investment. So I think that there's enough venture money out there and enough interest in devices now that these companies should be able to do those kinds of studies. In fact, I think we should push those requirements out to all product areas so that, for example, in peripheral interventions where they're not doing evidence-based studies yet, they need to start doing them.

Fitzgerald: I don't think you can talk about evidence-based medicine and a start-up in the same sentence. I think the focus and the milestones that a start-up has to achieve with regard to preclinical proof-of-concept and then first-in-man results are addressing a very focal issue and will potentially lead into evidence-based medicine. But that's not the role or the financing structure that a start-up should ever think of embarking on. And if they have to do an evidence-based trial in order to prove their concept, that's not a fundable event. There's a disconnect here between what the capitalization and the scientific milestones need to be in a start-up with respect to evidence-based medicine, and the goals that need to be put forward once that technology is housed in an arena that needs that evidence-based medicine, which is at a later stage of development. For example, take these new drug-eluting stent technologies: once you get them into the big companies, then scientific evidence is very important for penetrating into the market, but that's not a role nor even should it be on a milestone-driven cap chart for a start-up.

Grube: I completely agree with that. I think the beauty of start-ups is to develop things and bring them to the proof-of-concept stage. Everything that goes beyond that, including evidence-based randomized trials, is something that is simply not fundable for a start-up company.

But doesn't that produce a kind of Catch 22: many start-ups look at evidence-based medicine as a boost to adoption, almost like an implicit marketing message for their device. Yet, if we wait until a product resides in a large company before conducting randomized trials, that may limit small companies' adoption and commercialization efforts, which may inhibit innovation.

Fitzgerald: Sure, I think scientific-based evidence covers a broad spectrum that runs from a focused registry in a high-risk population to a broad randomized trial in a medium-risk patient subset, with the latter representing your big market opportunities. So, for example, when we look at percutaneous valve technology, we're going to go after a very narrow subset and then eventually will get into that big market. But that's not what the start-up should do because that's not what they're good at. They should leave that to the arenas that have to be responsible for that large market penetration eventually. For start-ups to get at least evidence that their technology is going to be clinically helpful is important. But, evidence-based medicine, per se, in terms of randomized trials, I don't think is a smart use of capital or expertise in the start-up arena.

In the drug-eluting stent market particularly, we've seen significant use of non-inferiority studies. Are those a short cut to establishing clinical or scientific validity and will we see the increased use of non-inferiority studies in product areas other than DES?

Grube: Obviously drug-eluting stents have emerged as a market unlike any other device we've seen before, particularly in terms of the size of the market. I think the use of non-inferiority studies is particularly applicable to the drug-eluting stent arena because there are now two primary players [Johnson & Johnson 's Cordis Corp. 's Cypher stent and Boston Scientific Corp. 's Taxus stent] and there's so much money involved that people are more concerned about non-inferiority than they have been before in other product areas where there generally were more options for alternative technologies. In drug-eluting stents right now, we're also dealing with a very complex approval process that large companies are having to adjust to or risk being excluded from the market. So in the particular case of drug-eluting stents, for now at least, non-inferiority studies are the best methodology for companies to use.

Another issue arising in the DES context is the use of surrogate clinical markers, such as late lumen loss, instead of randomized clinical events, as another way to ease the clinical trials process. Are surrogate markers a valid substitute for clinical outcomes?

Grube: I'm very grateful for this question because we're going through a transition in how physicians view the issue of whether late loss is as good as clinical events in monitoring restenosis. This whole issue of the importance of late loss emerged with the discussion of the results of Medtronic's ENDEAVOR trial. If we go back to the bare metal stent era, the clinical events were the end points that we looked at in randomized trials. Late loss really became important when we started to be able to significantly reduce restenosis with drug-eluting stents. In terms of talking about the efficacy of a drug-eluting stent, I would still rely on late loss. Whether that translates into clinical events, my belief is that will be determined over time and the ENDEAVOR trial might help us figure that out. But for me now to say, "Let's forget about late loss and just look at the clinical endpoints" is turning the wheel backwards. For example, if a stent had a 0.6 late loss number with good clinical outcomes, that's very good performance, but it's not as good we're seeing with Cypher and Taxus. When we did cases with the Devax bare metal stent, we had 0.5 late loss with good outcomes but people don't talk about that because that's not as good as the drug-eluting stents. Now everything is viewed from a Cypher/Taxus perspective, but I don't think it is good to completely forget about late loss and only look at the clinical endpoints.

Fitzgerald: This is a great example of the kind of question we were talking about previously and that is, if I'm a start-up with a new drug-eluting stent, I sure as heck am going to point towards late lumen loss as my preclinical proof-of-concept because for a reasonably small number of patients in a registry fashion I can figure out whether I am more like bare metal or more like drug-eluting. But eventually, when that technology is taken into a bigger arena and needs randomization, the late lumen loss becomes in my estimate a less important configuration. What's really important is how the patients do and whether the results from the drug-eluting stents are comparable to other technologies that we have available today. If I can produce results similar to what's out there today, I'm not sure I need to look at all those thousands of patients' late lumen loss to appreciate the benefit of this technology.

Stone: I don't think late loss is actually a very good surrogate marker. Angiography is a good surrogate in general for clinical restenosis and I think that obviously you can have fewer events if you track patients with angiographic follow-up. The problem is safety. And in device trials, to look for significant outcomes such as MACE [major adverse coronary events], death, stent thrombosis, and myocardial infarctions--you need a lot of patients. It's a double-edged sword. I think it is appropriate that, with devices that utilize new molecular entities, the FDA is requiring experience in several thousand patients. Think about it this way: with drug-eluting stents, we're now implanting around 1.5 million permanent prosthetic devices per year in the coronary arteries of about one million people in the United States alone. That's extraordinary—it is by far the most widely used prosthetic implant in the world. I think it's very appropriate before we get anywhere close to those kind of numbers that we ask for data on a thousand or two thousand patients. That doesn't strike me as unreasonable.

Last spring, when Medtronic released the first ENDEAVOR trial results, even though the numbers were good except for the late loss figures, the industry buzz was that this was bad news for Medtronic and good news for the other drug-eluting stent competitors. Was that concern overblown or did the late loss data justify that response?

Fitzgerald: I think all of us, both in the industry and in the scientific and clinical communities have to understand that we are all learning together here. And that means that what we might have thought to be a paramount surrogate endpoint like late lumen loss may not, in fact, be the most important thing because we have a lot to learn in what is still a newly emerging clinical field. Remember, we've only been working with drug-eluting stents scientifically and clinically for a few years now. We should all be humble enough to admit that maybe late lumen loss isn't the best surrogate. I am convinced that late lumen loss is important, but it's not the whole story.

There's another part to the story that we can't lose sight of when we're talking about non-inferiority trials and efficacy. And that is the relationship between late lumen loss and safety, not just efficacy. I am not sure complete annihilation of the vascular response, which is intimal hyperplasia, is healthy. I don't think completely filling the lumen with intimal hyperplasia is healthy either. But one results in morbidity and one in mortality, and it's important as we're trying to address patency here that we always keep our mind on safety issues because those could potentially present themselves as mortal issues such as late thrombosis.

Right now, the drug-eluting stent market is a two-horse race. At this conference, there was a session profiling eight or nine other drug-eluting stents that are being developed. Next year, there probably will be at least a half-dozen additional competitors. Five years from now, how many viable drug-eluting stents will be on the market?

Grube: Obviously I like the competitive part of this process because I believe that the development of new drugs, new coatings, and new stent concepts drives medicine forward. That's progress. The problem that we're facing now is the regulatory process because there are drugs involved, which creates a completely different time frame and most small companies simply cannot afford to endure this process. That is something that I'm concerned about because, in order to go through this regulatory process, it takes time, an incredible amount of money, and extensive documentation for the drugs. I'm afraid that, while small companies have brilliant ideas, whenever a drug is involved, the regulatory process gets very complicated to the point where I'm not sure whether even mid-sized companies can afford it. If you look at what's happening now with drug analogs, the big companies often try to impact the development of these technologies by litigating against small companies, as is now the case between Boston Scientific and Conor Medsystems. So in a way I'm afraid we are stuck with the two big players for now and maybe several other large companies in the future, including Medtronic and Abbott, depending on whether and when their drug-eluting stents come out. But all of the other companies trying to compete in this market face an unbelievable struggle to surface, not because their products are bad or good, but because of the costs and complexities of the drug regulatory process, which is completely different than the typical device technology development process.

Fitzgerald: I believe that the dynamic process that has always characterized the stent market will absolutely necessitate that the drug will eventually become a commodity. The drug in drug-eluting stents will be taken out of the equation. The drugs will be commoditized primarily because the device companies don't have the patience to wait for five years and don't have the knowledge base to put together the drug master files that regulators require. So the folks who have pharma in their holsters will be better at turning out the drugs. But turning out the drugs is not going to be what ultimately improves the technology. Innovation is far better than litigation and what's going to happen is that the delivery performance of a stent is going to re-emerge as the critical component for success in this market. This is because ultimately a drug is only as good as the ability to deliver it where needed. That is going to put the emphasis back on the stent platform and that's where the innovation is going to come from over the next five years—the platform, not the drug. And that will benefit the small start-ups that are delivering drugs a better way and there's a whole host of them up and down Highway 101 in the San Francisco area and around Rt. 128 in the Boston area, and Conor is only the tip of that iceberg.

Stone: Five years from now, I think there will probably be six or seven viable drug-eluting stent companies. I think the field's going to continue to grow. Obviously the reimbursement is there to be able to drive innovation and we need improved devices. We need to eliminate stent thrombosis so we need more thrombo-resistant stents. Also, as we start doing more complex cases, as you're starting to see now, restenosis rates are going to go up, which will also create a need for better devices. We've got a group of companies poised with good products to get into the space and that's good because that is going to really drive innovation for the next generation of improved devices.

If Boston Scientific prevails in its litigation against Conor Medsystems, will that send a chill through this industry or is that just business as usual?

Fitzgerald: Name the last time that litigation sent a chill through the med/tech industry in the last 15 years or so. At the end of the day, I don't think that litigation ever prevails. And it's not healthy for patients and it's not healthy for innovation. Litigation will foster posturing and competitive maneuvering, but it will never kill innovation.

As you noted, restenosis rates will increase as interventionalists start using drug-eluting stents for more complex cases, and as the results of real world registries such as ARRIVE are reported. There has also been research done by people like David Cohen at Harvard noting that drug-eluting stents are being used for a much broader patient population than will economically benefit from these devices. Given the cost constrained environment, which has restricted drug-eluting stent utilization dramatically in Europe, and that most people agree that we are continuing to see improvements in bare metal stent technology, could economics drive a resurgence in bare metal stent usage or has that ship sailed?

Stone: That ship has mostly sailed. We haven't been able to push the late loss of bare metal stents much below about 0.8 millimeters. Now if we can get it down to about 0.6, which isn't that big a drop, then you might start getting some competitive results, but I've not yet seen bare metal stent performance that can really get below that floor of 0.8 which suggests that we may have reached the limit of how an artery is going to respond to a metallic stent. That's why I'm more interested in bioabsorbable stents, which is the next generation that is designed to leave the artery in the pristine state that existed before atherosclerosis started developing.

I also don't think that the real world registry data is going to have a major impact, frankly. I'm kind of outspoken on the subject but I think you get limited information from these registries. Registries can be useful for specific purposes. For example, large registries will be very useful to look at low frequency events such as stent thrombosis if the reporting is honest, and maybe for things like hypersensitivity reactions. But I think we're getting a lot of under-reporting in registries of restenosis events and target lesion and target vessel revascularization. For example, if you look at how great the outcomes are in the registries in general with drug-eluting stents compared to what we see in randomized trials like SIRIUS and TAXUS IV and TAXUS VI: despite the fact the registry has much more complex patients, supposedly 98% of them are symptom-free at the end of the year. I don't believe that for a minute.

Fitzgerald: The bare metal stent ship has long since sailed. What will happen is that eventually we will see price promotion on drug-eluting stents. But we will never see a recapturing of bare metal enthusiasm, at least not in the cardiovascular system. That said, I think that like no other time in the last 10 years we are seeing an opportunity for start-ups in the med/tech arena that drug-eluting stents have created. There are opportunities here that the big companies cannot spin quickly enough on.

One of the emerging therapeutic areas that has been discussed in some length at this conference is vulnerable plaque. Depending on whom in the industry you ask, vulnerable plaque is either the biggest hype or the Holy Grail. In one session, Peter, you said that the enthusiasm for vulnerable plaque has outpaced the level of scientific investigation. What is the current understanding of vulnerable plaque from both a diagnostic and a therapeutic perspective, and does vulnerable plaque lend itself to device therapy, which historically has been more focal and mechanical, or is it more likely to respond to a more systemic treatment such as drugs?

Fitzgerald: We've gotten pretty enthused in the device industry over the last couple of years about vulnerable plaque, mainly because we've never actually been able to direct anything other than a mechanical solution into these obstructions. Now we're bringing both a mechanical and biologic approach to these obstructions. I think the enthusiasm has really outpaced the incremental scientific knowledge that we've accumulated in this field, but that's okay. Being able to diagnose and have some surrogate to track the fact that we've been able to affect the biology with these technologies is going to be very important for establishing the underlying natural history, which is a critical part of the scientific pathway for understanding and classifying vulnerable plaque.

The device approaches that we're currently considering will not, however, be the solution to the problem, which is the second part of your question. It will teach us an awful lot about the underlying condition, but it will be the steps, it won't be the stage. The stage will be either targeted systemic therapy or regional coronary tree therapy. But if it's going to take five years to develop these natural history studies and bring these device technologies to fruition, we might miss whatever opportunity may exist for focal device therapies and we may also even miss the opportunity for regional device treatments because the field may be overtaken by systemic approaches such as drugs.

Vulnerable plaque is like acne of the coronary arteries. A band-aid on acne is a partial solution, so unless you have at least a regional, if not a systemic, therapy, you're not going to get to the disease substrate, so it's possible that vulnerable plaque could essentially defy device therapy.

Other emerging therapeutic areas that have been discussed at this conference include tissue engineering, gene therapy, and stem cell therapy. We are already seeing the application of some of these approaches, such as Orbus Medical Technologies' use of endothelial progenitor cells (EPC) on a stent. Each of these areas has its own unique dynamics, but how far away are we in terms of therapeutic applications of these technologies? Are they still science projects or will we see applications within our lifetimes?

Grube: While I'm not an expert in this field, I'm obviously looking at these areas very carefully, but I'm also a little skeptical. Among our colleagues, views vary widely. Marty Leon, MD [Columbia University Medical Center and CRF] is of the opinion that the early results are very promising so we have to pursue this. And then on the other side is Dan Burkhoff, MD, PhD [Columbia University School of Medicine], who doesn't see this as even being close to clinically ready in a wide range of applications within the next five years. Personally, I would think science and human curiosity would bring this field forward. It's not going to be ready in five years, and I really don't know when it will happen but it's going to come. We will see something that is effective. I do agree with Dan that small studies don't mean very much, in fact some people say they don't mean anything, and in terms of proof-of-concept, I am not convinced we are there yet. So, I am a little bit skeptical, but I think it's a very interesting approach and it's going to come at some point in time.

Fitzgerald: As you noted, the areas you mentioned are each quite different. The use of endothelial progenitor cells is an interesting application. We're always oriented towards stopping the healing process after we've injured a vessel. Being able to encourage the healing process is a great area to investigate and that's much closer to fruition than, for example, cell therapy for the engrafting of myocardial cells. That is a long way away. But the EPC technology, which rather than keeping things from healing actually encourages healing, is an example of what we've been discussing here concerning the opportunities that exist for start-up company innovation triggered by drug-eluting stents. I think one of those areas could be enhanced healing. Whether it's done through the EPC technology, or whether it's done in other ways, it's important to not only look at getting rid of neointimal hyperplasia, but also maybe healing it sooner. Most of the other areas such as cell therapy, and genes for engraftment and for revascularization in the myocardium, are still in the science-project stage and won't be in our cath labs or in reality for a minimum in my opinion of at least five years.

Stone: The problem is that these therapies now are being primarily directed at heart failure, whether it's acute heart failure and acute myocardial infarction or chronic heart failure, so our information is limited. And I agree that it's mostly a science project at this point. We have only one study with any sort of control, and we obviously need controlled randomized trials. Some of those are being done. We need double blind controlled randomized trials. You saw what happened with the DIRECT trial for laser myocardial revascularization [indicating that the technology was ineffective, despite some early positive results] and the same thing can absolutely happen here. Those studies will be done and I think within about a year to a year-and-a-half, we'll either have proof-of-concept or we'll be back to the drawing the board. I'm cautiously optimistic, maybe a little bit more so than Peter or Eberhard. I think within a year to a year-and-a-half that if we have proof-of-concept then you'll see an explosion in groups that are taking this to a larger scale.

As we see advances in percutaneous technology to enable the interventional treatment of heart valve repair and replacement, carotid stenting, peripheral vascular disease, and structural heart defects such as PFOs, is the practice of interventional cardiology going to change to one where we have a series of subspecialties or will interventionalists continue to perform a wide range of these procedures in the cath lab?

Stone: I think the answer, unfortunately, is both. I say unfortunately because even now, I believe that there are too many low-volume operators just performing coronary interventions, and that does nobody any good because, to keep their outcomes good, they will only do simple straightforward cases which in and of itself is fine if they were to refer more complex cases to operators who can do more complex cases. But, because of the nature of human beings and referral patterns and the business of medicine, they may be more likely to refer more complex cases to surgery than they would to a competitor who could do an intervention.

Referring some patients to surgery is one problem with low-volume interventionalists. But there's another. As you pointed out, our practice is going to get more and more complex as we are able to percutaneously perform procedures such as transeptal punctures to do valve repair and replacement, and left atrial appendage closures. These procedures will be extraordinarily complicated. One of the reasons I haven't elected to do peripheral interventions is because I only want to do what I can be absolutely expert at. I've made that personal decision. But many other people will say, "No, I've got to be doing everything if I'm going to have a competitive advantage." So you get low-volume operators in the coronaries and peripherals and in the treatment of structural heart disease and in electrical therapies, and that's going to be an issue.

At CRF, you have long been known for providing excellent training of fellows and physicians. At TCT, you've been focusing more on the use of simulators for training on interventional procedures. What role do you see simulators playing in the future and how far are we from simulators becoming an integral part of the formal physician training process?

Stone: I think simulators are going to become increasingly important in the way we train physicians. This will be particularly significant for some of the orphan or low-volume procedures that you just never get enough experience with doing, such as perforations and the more unusual complications that you'll be lucky if you see once every two years. And of course the FDA has mandated that simulators play an important part in carotid stent training, and I think that will also be true for valve therapies and for all the newer interventional procedures that will be coming along, so that eventually simulators will become an essential part of what we do.

Last year at TCT, a patient died during a live case transmission, and here at JIM this year, a perforation occurred during a live case. Do you look at those cases and say that there's always a risk of these things happening, or do these occurrences cause you to think that maybe live cases are too risky?

Stone: I don't think that live cases are too risky if you have the right operators, and here at JIM and at TCT we have the top operators in the world. And while they're doing complex cases, when you realize that in the fifteen-year history of TCT, there have only been two deaths in the thousands of cases that have been performed on incredibly complex, high-risk patients, actually I think that the mortality is much lower than you would have expected. You've got to realize that in live cases things will happen and you just have to be prepared to see that. In fact, it's extraordinary how often the cases go very well and we get great results. Most importantly, we can't forget that these cases are highly educational and that's how physicians learn.

Let's end by returning to the dominant subject for interventionalists and that is drug-eluting stents. During one of your JIM presentations, you stated that there was 97% penetration of drug-eluting stents in the US. If you talk to European industry executives, they will say to you, "Well, we know we're lagging, but we think we'll catch up." Do you think Europe will catch up to the US in drug-eluting stent utilization?

Stone: It will depend on reimbursement, but I think it eventually will happen. The only reason Europe is not using as many drug-eluting stents is lack of reimbursement. That's clear. You've got great physicians in Europe and they know the data and the outcomes. I'm sure they're very frustrated because their hands are tied. On the other hand, what could potentially hurt drug-eluting stents is if we don't start getting a handle on late stent thrombosis and some of the other issues that are starting to emerge as being potential problems.