Cardiovascular Business invited representatives from the four major stent manufacturers to discuss the challenges and future outlook for drug-eluting stents (DES). Participants in the roundtable discussion are:

• Chuck Simonton, MD, chief medical officer at Abbott Vascular (XIENCE V)
• Keith Dawkins, MD, associate chief medical officer at Boston Scientific (PROMUS and TAXUS)
• Campbell Rogers, MD, chief technology officer at Cordis (CYPHER)
• Sean Salmon, general manager at Medtronic (Endeavor)

Moderator: C.P. Kaiser, Editor, Cardiovascular Business

The utilization of drug-eluting stents (DES) has been fluctuating in recent years. Do you think it will decrease, plateau or increase and why?

Sean Salmon, Medtronic: Since February of this year, we have seen in the U.S. market an increase in the use of DES from the low 60 percent range to the mid-60 percent range. The reason for the uptick is probably multi-factorial, but I believe the launch of Medtronic’s Endeavor DES in the U.S. market [February 2008] may have helped in some regard. I also think that physicians and patients have gained a general appreciation around the overall benefit that DES provide.

Campbell Rogers, MD, Cordis: I agree that an increased comfort level with DES in the marketplace is offsetting some of the perceived negative data that has come out over the previous 18 months. There also have been publications in the last few months demonstrating reassuring data—at least about CYPHER—regarding lower mortality rates compared to bare-metal stents (BMS). These studies have appeared in quality publications. In that setting, the news has been reassuring to practitioners.

Chuck Simonton, MD, Abbott Vascular: The data that have emerged more recently after extended follow-up show that the safety of DES is equal to, or even better than, non-drug-eluting stents. Also, some of the negative reverberations of the COURAGE trial are quieting down as we see that stable angina patients with documented ischemia who were treated medically are eventually finding their way back to the cath lab. Confidence in DES will continue to improve, particularly with the release of Endeavor and now with the XIENCE V [approved July 2008].

Keith Dawkins, MD, Boston Scientific: With the increased awareness of the data that has now been published from numerous trials and registries since the concerns that were initially brought up in 2006, physicians and referring clinicians are becoming more confident. We have seen a sustained increase in DES penetration and, indeed, in PCI penetration over the first half of this year. We anticipate it will get back to the 2006 levels within the next few months.

What can the industry do to neutralize sensational negative press coverage that contributed to the slide in DES utilization?

Salmon: This controversy has highlighted that there is a need for a better affinity group among interventionalists to define and protect the field. Our professional societies aren’t as mature or prominent as they need to be.

Dawkins: We’ve been working as an industry with AdvaMed [Advanced Medical Technology Association] to deal with some of these issues. Sometimes it is better if we share our communication with the press as an industry group rather than as companies. The way we will be judged as successful or not will be based on clinical science. At Boston Scientific, we have the TAXUS program, now with more than 45,000 patients studied. We continue to look for clinical science to provide us with the answers.

Rogers: All of us have been part of the peer-review process on both sides and we have incredible faith in those mechanisms. What happened with DES in the past several years was the data came out in forums that were not peer-reviewed medical journals, such as at meetings.

An additional side to this is that we have to continue to undertake rigorous well-designed clinical studies that answer clinically important questions, which is a slightly different approach than having clinical studies purely to get a specific device approved. For example, all four DES manufacturers, as well as two of the manufacturers of antiplatelet medications, are part of an ongoing constructive collaboration under AdvaMed. We are in the beginning stages of designing a trial with approved devices aimed at identifying the best way to manage patients with antiplatelet therapies for optimal long-term outcomes.

What is being done to reduce the cost of dual-antiplatelet therapy? Are you developing coatings and polymers that will help reduce the duration of therapy?

Simonton: The FDA-mandated AdvaMed study, as mentioned earlier, will deliver more clinical data to help us determine the optimal length of dual-antiplatelet therapy and help us determine variables in patient selection that make a difference. Regarding making stents safer, we all have ideas in the pipeline. One immediate way is to reduce the acute injury related to the procedure with thinner struts, polymers that are bioabsorbable and lower doses of anti-proliferative medicine. Abbott is specifically interested in—and is probably the furthest along in its development—a fully bioabsorbable DES, which has the potential to shorten the time a patient might have to continue Plavix for the concern of late stent thrombosis. This stent not only has a polymer that bioabsorbs on the surface of the metallic stent, but the whole stent would actually bioabsorb over about 18 to 24 months.

Salmon: There is another point of view here that the antiplatelet drugs that are used adjunctively with stents also prevent further atherosclerotic events, whether in the carotid circulation or other places in the coronary tree. The avoidance of further atherothrombotic cardiovascular events might make these drugs cost-effective. That premise needs to be further evaluated in clinical trials.

With regards to device development, the available data so far on the Endeavor stent suggest that we don’t see an excess rate of stent thrombosis, particularly from one year and beyond. Those data are being evaluated in a prospective randomized trial with an active control. Like everyone else, we have been working on resorbable stent technology, but even with those you will induce some inflammation, which has been implicated in both thrombosis and restenosis. We feel comfortable that we have a device right now that doesn’t seem to have problems that existed in the early iterations.

Rogers: Antiplatelet therapy is an area where there is ongoing pharmaceutical innovation such as with the Eli Lilly drug Prasugrel. Also, there are mechanisms for patients who cannot afford these medicines long term. Johnson & Johnson, of which Cordis is a subsidiary, is a member, for example, of Together Rx, which provides discounts to prescription medicines for people without health insurance.

In terms of our CYPHER stent, we don’t see a difference in late thrombotic events compared with BMS as we gather data from more patients over longer periods of time. We need to take it to the next step: to find ways to prevent thrombotic events altogether. Our research strategy is two-fold. The first is the use of a bioabsorbable polymer on our next-generation devices, the Conor platform, which is being evaluated in two clinical trials outside the U.S. and soon to be tested in this country. The second is the ability to add additional drugs, which will lessen the rate of thrombosis even compared to BMS. The Conor platform enables us to do that, to add antithrombotic or antiplatelet drugs.

Dawkins: As Dr. Simonton mentioned, we have been tasked by the FDA, working through AdvaMed, to address this issue and have had a number of meetings as an industry group to develop a trial to answer the important questions of how much antiplatelet therapy is needed and which groups of patients need the therapy for extended periods. All of the industry is interested in reducing that need in all patients. We are working on programs to reduce the dose of drug, reduce the polymer load, and therefore hope to mimic, if you will, the duration of dual-antiplatelet therapy that is required for BMS, which is 30 days. We have two programs developing biodegradable stents, which we hope will allow us to dispense with the need for dual-antiplatelet therapy in many patients after a very short period of time.

When can we expect fully dissolvable stents?

Simonton: Based on the current FDA guidelines for DES that have either a new metallic platform, new drug, or new polymer, the development cycle is going to be five to seven years. Abbott just completed its first in-man pilot with a bioabsorbable everolimus stent, which was published in The Lancet earlier this year. We anticipate the two-year outcomes in those patients will be presented at the TCT conference in October.

Dawkins: We have access to two fully biodegradable stents and are working in that field. There are challenges in relation to completely biodegradable stents, and I think Dr. Simonton’s assessment of five to seven years is appropriate.

Salmon: I think it’s more on the seven- to 10-year range, if at all. There are numerous trade-offs to these devices. You have to ask yourself, what problem are you trying to solve. For fully resorbable stents in the coronary circulation, I am circumspect that there is a need. Maybe for other vascular beds there is a clearer case. I do see, within five years, stents that have resorbable carriers through the polymers themselves, resorbably leaving behind the bare-metal stent or some basement membranes as well.

Rogers: One of the advantages of Cordis is we have partners within Johnson & Johnson. We have within our Ethicon franchise, a polymer expertise group called the Center for Biomaterials and Advanced Technology. In collaboration with them, we are working on an internal program for a bioabsorbable stent. I will tell you there is a fair amount of skepticism in the overall assessment of the market, especially in the coronary space. And to borrow Mr. Salmon’s phrase, what problem are we solving? For other vasculature beds, there may well be more merit.

In terms of bioabsorbable carriers on BMS, that’s the area where our focus is with the Conor platform. We have two ongoing trials. It’s not five years away, it’s happening now.

Some data suggest that no significant differences in deaths or myocardial infarctions exist between groups receiving either the DES or BMS. Why, then, should interventional cardiologists use the more expensive DES?

Rogers: I would quibble with your premise. As we look at increasingly robust data sets from increasingly complex patients, there are clear differences in the pattern of adverse events that are falling out between the different DES. The Western Denmark Heart Registry, for example, presented similar outcomes for DES versus BMS, consistent with the premise you just put forward. However, when the investigators broke out the two different DES, CYPHER and TAXUS, there were dramatically different patterns. CYPHER performed as well or better than BMS for rates of death and MI, while TAXUS performed worse. Additionally, the rate of re-intervention is clearly lower with CYPHER than with TAXUS.

Simonton: I agree with many of the comments Dr. Rogers made, but much of the data he mentions are from large registries. Regarding the XIENCE V, our data from large randomized trials, the SPIRIT III trail, for instance, show very interesting outcomes in relation to death and MI at one year, particularly with periprocedural MI, which are trending lower for the second-generation stents. Deliverability is part of the problem with the first-generation stents and maintaining that benefit over time is important.

Regarding DES versus BMS, there will be the largest pooled analysis of registries coming out of the Cardiovascular Research Foundation by Dr. Ajay Kirtane. It will show that the mortality rate actually favors DES.

Dawkins: It’s clear beyond doubt that DES reduce the need for repeat procedures by reducing target lesion and target vessel revascularization. The only open question was the issue of late stent thrombosis. At ACC 2008, Dr. Gregg Stone presented a mega-trial incorporating all the available DES data from randomized trials and registries. It shows that DES are efficacious, essentially halving the chance a patient will come back for a repeat procedure. In the more complex patients, the off-label patients who are frequently treated in everyday practice, the evidence shows a reduction in hard end-points including mortality. Patients who have BMS also suffer from stent thrombosis and they may have an MI associated with repeat procedures. That risk associated with BMS is offset by DES. From the point of view of cost differentials between BMS and DES, the patient clearly prefers not to have to come back for a re-do procedure. Therefore, we would favor DES for the majority of patients.

What will the shelf life be of the newer DES?

Salmon: The shelf life we have for the Endeavor stent in the U.S. is 12 months. We just received approval for 18 months in mid-July and it is 24 months outside the U.S.

Rogers: Our current shelf life in the U.S. is three months and outside the U.S. it is up to 12 months in some parts of the globe.

Simonton: The XIENCE V stent is currently approved for one-year shelf life and Abbott is in the process of putting through all of the applications necessary to extend that to 18 months.

Dawkins: The shelf life for the TAXUS stent in the U.S. is 18 months, and for the PROMUS stent 12 months.

What are you doing to measure and improve the safety of the next generation of stents?

Dawkins: We are looking at ways of reducing the drug load, reducing the polymer load and switching from durable to biodegradable polymers, as well as looking at unidirectional delivery of the drug. Everybody in the field accepts that these measures will be beneficial for the patient. The area of potential difficulty is to work out whether doing so improves the function of the device compared to the devices we have now.

Salmon: The most important thing to figure out is whether there is a safety issue that needs improvement. We do have ongoing trials, half enrolled toward their 8,800 patients, randomized with a primary endpoint of ARC-defined definite and probable stent thrombosis at three years with an active control. They will prove definitively whether this device has an issue that needs to be fixed.

We also are always interested in continuously improving the technologies and we are accomplishing that in a couple of ways. We have an active polymer library, where we create highly biocompatible durable polymers that degrade without creating acid that induces inflammation. We also have completely non-polymeric stents with a nanoporous surface.

Rogers: We are looking at improving upon what we think are fairly similar patterns over time with CYPHER and BMS both in terms of thrombosis and to lessen the rates of thrombosis to levels lower than even for BMS. It’s a two-step process. The first step is to introduce a bioabsorbable polymer, which allows the effect of the drug in reducing restenosis, while the polymer goes away. The next step is to add active anti-thrombotic activity to the device in addition to sirolimus to prevent restenosis.

Simonton: Abbott has already made an impact on patient safety with the XIENCE V platform, which is trending very strongly in terms of reducing death and MI compared to first-generation DES. A stent thrombosis rate of 0.2 percent to 0.3 percent, such as with the XIENCE V, may be difficult to improve upon, unless it’s with a stent that goes away completely. About two years after treatment with a bioabsorbable stent, the vessel can get larger; it can actually respond more normally as most vessels do to vaso-reactants and be more like a normal vessel. So, Abbott’s strategy is to have a safe non-inflammatory fully biodegradable polymer-based stent that will lead the vessel back into its native state, allowing it to accommodate future changes similar to the way a previously untreated vessel might do.

Because DES choices in the U.S. have doubled over the past year, how do you intend to differentiate or market your product?

Salmon: We are sticking with what the evidence says about our device. There has been a lot of focus in the marketing of these devices on surrogate markers and angiographic markers. Our focus has been on the clinical benefit gained by a patient who has a procedure. We have proven in our evidence that our DES is superior clinically to a BMS and that we are not inferior to two of the present devices in terms of clinical events. Ease of use, of course, is an easy marketing focus, but it’s the quality of the long-term data that we have got, with an excellent safety record and an interesting and perhaps differentiating emergence of a stable clinical result for target lesion revascularization rates out for four years that are unchanged from the three-year mark and very close to the two-year mark.

Rogers: Traditionally, in the BMS era there was a tremendous focus on the speed with which a device could be introduced, so-called deliverability, with very similar outcomes across BMS. Now, as we see differences emerging in the long-term performance of DES and superiority of some DES over others, it’s that long-term benefit that ought to drive the choices of practitioners and administrators. That’s certainly where our focus on differentiation would be.

Simonton: The XIENCE V stent from Abbott Vascular is the first DES to show superiority over another DES in two randomized clinical trials. What matters to patients are the clinical outcomes, such as major adverse cardiac events. The data from the SPIRIT III trial show our low event rate with XIENCE V is holding up and even becoming numerically wider at two years with stent thrombosis rates, lower than TAXUS, the current market leader. During the next year, we’ll have over 14,000 patients internationally in trials looking at these types of safety issues. The position of Abbott Vascular with XIENCE V is clinical superiority over the first-generation DES, based on available data from two randomized clinical trials, and we are going to continue to innovate on that.

Dawkins: In the U.K, where I come from, there are 22 different DES with CE mark. So the decision for physicians becomes more complicated. The rationale for choosing one over another can be channeled into a number of areas. Physicians will look at the patient outcomes data. They also will be interested in the handling characteristics of the stents, the effectiveness of the drug and the cost of the stent. Boston Scientific is in the unique position of having two DES products, the PROMUS and the TAXUS stents, which have two platforms, two different drugs, two different delivery systems and two different polymers. We would hope that interventional cardiologists will appreciate different products and choose appropriately.