Ashley B. Boam, BSE, MSBE: Welcome to this Medscape expert commentary on drug-eluting stents (DES). I'm Ashley Boam, Chief of the Interventional Cardiology Devices Branch of the US Food and Drug Administration (FDA) Division of Cardiovascular Devices. Our branch is responsible for the regulation of coronary DES that are used in the United States. DES are tiny, metallic scaffolds that are coated with a polymer containing a drug that is released over time to prevent restenosis. These catheter-based devices are currently approved for the treatment of symptomatic coronary artery disease in patients undergoing elective percutaneous coronary interventions, otherwise known as PCI procedures. Compared with bare metal uncoated stents, DES are associated with a lower rate of repeat revascularization procedures.
Andrew Farb, MD: I'm Andrew Farb, a cardiologist and cardiovascular pathologist. I serve as a Medical Officer and Senior Reviewer in the Interventional Cardiology Devices Branch. One of my main roles at the FDA is to review proposed clinical trials to evaluate new stents as well as to assess the data submitted for FDA approval to allow marketing of a new stent in the United States. Today we are going to talk about the approval process for DES, what kinds of data are needed to support new indications for use of these devices, and some of the challenges in treating coronary artery disease yet to be solved and new technologies under development.
The FDA Approval Process for DES
Dr. Farb. Ashley, the approval process for DES seems long. Could you give us an overview of what kind of data the FDA are looking for in an application of a new DES?
Ms. Boam: Sure. A DES is a combination product consisting of 3 important individual components: the stent, the polymer, and the drug combined together in the finished product. The FDA needs information on how the stent performs, which starts with laboratory bench testing of the stent and polymer coating, which may be permanently affixed to the stent or may be intended to degrade over time, as well as some safety information about the drug component. If the drug has been studied for some other use, this information may already be available. For the complete finished DES product, we ask for studies to evaluate biocompatibility and how the drug and polymer coating performs; that is, does the coating remain in place on the metallic stent or are small particles released downstream as the stent travels through the arteries to the implantation site? Testing of the DES in an animal model, usually DES implantation in pig coronary arteries, provides important in vivo safety information on local vascular responses.
Once acceptable preclinical data have been obtained, we ask for 1 or more clinical studies to demonstrate the safety and effectiveness of the device in human patients. These studies usually involve evaluation of a composite primary endpoint of cardiac death, myocardial infarction, and need for repeat procedure involving the lesion where the stent was placed. This primary endpoint is assessed at 1 year, but in addition, patients are followed for up to 5 years to look for any late safety signals. As you can see, our focus is on clinical outcomes that are important to patients and physicians: death, myocardial infarction, repeat procedures. We also ask for a smaller subset of patients with protocol-mandated angiography and intravascular ultrasound to assess healing responses and how well the stent is apposed to the artery wall, both immediately post-implantation and in the long term.
Yes, the approval process may seem long, but one should realize that DES are complicated, significant-risk products that are implanted in hundreds of thousands of patients each year. In order to okay a new stent for use in the United States, we need evidence that the stent is reasonably safe and effective and that the benefits outweigh the risks. As I noted in my initial comments, the DES that are currently marketed in the United States are approved for use in patients undergoing elective procedures.
Duration of Dual Antiplatelet Therapy and the DAPT Study
Ms. Boam: Andy, what is next in terms of new indications for DES?
Dr. Farb: It's important to recognize that the pivotal studies for the currently approved DES had enrolled clinically stable patients with treatment of 1 or 2 relatively noncomplex coronary lesions. As we know, many patients present with acute coronary syndromes, and the anatomy of coronary disease is often quite complex and involves multiple vessels. To address the clinical benefit of DES stents in high-risk patients and lesions, several DES trials have recently been conducted or are just getting under way. For example, the HORIZONS-AMI study evaluated the use of DES in patients with ST segment elevation myocardial infarction (STEMI). The culprit lesions in STEMI patients are fundamentally different from stable lesions. The HORIZONS-AMI study addressed the question of whether a DES implanted in a STEMI lesion would be associated with a lower rate of repeat revascularization procedures -- that is, superior effectiveness, with a similar safety profile compared with a bare metal stent.
Another exciting study just getting under way will evaluate the use of DES in unprotected left main artery lesions. The standard of care for left main disease is bypass surgery, but exploratory analyses from this recently completed SYNTAX trial, which looked at DES vs bypass surgery in patients with left main and 3-vessel disease, suggested that DES might compare favorably to bypass surgery in some left main patients. To address this question definitively, the EXCEL trial will randomly assign left main patients with select anatomic features to implantation of DES or bypass surgery. This trial will be a true treatment strategy trial. So crafting a set of endpoints that are important to patients and physicians, including death, myocardial infarction, and stroke, will define the short-term and long-term pros and cons of a percutaneous treatment vs open surgery for a critically important disease.
Clinical studies are also in progress to provide a greater understanding of the risk/benefit profile of DES in diabetic patients, an important high-risk subgroup, and to assess the safety and effectiveness of DES in complex coronary bifurcation lesions.
The Challenge of Stent Thrombosis
Dr. Farb: Even as we move forward with these new uses of DES, there are still some remaining questions regarding the currently approved devices. One of these is the thorny issue of stent thrombosis.
Ashley, this issue emerged as a big concern back in 2006. What do we know now about stent thrombosis and how has the FDA's approach to this issue changed over time?
Ms. Boam: Stent thrombosis or clot within a stent, although rare, is a serious issue, because when it occurs, it usually results in MI or sudden death. Stent thrombosis didn't originate with DES. Acute stent thrombosis, meaning stent thrombosis within the first 30 days, was an established rare catastrophic event with bare metal stents as well. What grabbed folks' attention back in 2006 were signals in ongoing studies and in the literature that DES might be associated with a higher rate of late stent thrombosis, that is after one year, compared with bare metal stents. The FDA convened a two day advisory panel meeting in December of 2006 to look into this issue further and concluded that when DES were used on-label, in other words for their approved indications for use, the rate of late stent thrombosis was numerically higher than with bare metal stents but not associated with higher rates of cardiac death and MI. However, it wasn't clear whether this latter finding was due to insufficient data or whether an increased rate of death and MI due to more stent thrombosis was offset by a reduced rate of repeat revascularization as compared to the bare metal stents.
When DES were used in more complex patients and more complex lesions, there was both an increase in the rate of stent thrombosis and in the rates of cardiac death and MI compared to on-label use, although not enough data was available to identify certain subsets of patients at higher risk. Since that 2006 panel meeting, we at the FDA have modified our recommendations for both pre-market and post-market studies of DES to evaluate this issue more closely. In pre-market studies of new DES, patient compliance with dual antiplatelet therapy consisting of aspirin plus a thienopyridine to reduce the incidence of stent thrombosis is monitored more closely and is reported in the product labeling.
Since the event rates in question are quite low, we also used data gathered in post-approval studies to improve the precision around the rates of stent thrombosis and cardiac death or MI. Most notably, because there have been signals that the rate of stent thrombosis after one year continues to increase over time, all post-market studies follow patients for five years, and the results are included in the DES labeling. For the DES approved and marketed in the US, the data we've evaluated suggests that in on-label patients the rates of cardiac death or MI remain comparable to those for bare metal stents. Probably the most significant initiative in this arena is still ongoing.
Duration of Dual Antiplatelet Therapy and the DAPT Study
Andy, can you tell us a little more about the DAPT study and what it will tell us when it's complete?
Dr. Farb: In addition to collecting more data on individual stents and rates of stent thrombosis, the FDA and others in the academic and clinical communities recognize that one critical unanswered question centered around the duration of dual antiplatelet therapy following implantation of a DES. In the initial DES trials, patients received dual antiplatelet therapy for three or six months, and premature discontinuation of dual antiplatelet therapy was the most important risk factor for stent thrombosis. The cases of stent thrombosis that occurred beyond one year suggested that a longer duration of dual antiplatelet therapy might be needed, but how long is long enough? In 2006 the cardiovascular professional societies issued guidelines recommending that dual antiplatelet therapy be continued for at least one year following DES implantation, but it was recognized that these recommendations were based largely on consensus opinion rather than robust clinical trial data.
Further, if dual antiplatelet therapy was to be extended, perhaps indefinitely, would the potential benefit of reduced rates of stent thrombosis be offset by increased rates of major bleeding. The FDA believed that a randomized trial was needed to address this question, and the DAPT trial was designed to address the duration of dual antiplatelet therapy in DES patients. Four DES manufacturers, two pharmaceutical partnerships, and an academic research organization working together are conducting a trial of over 20,000 patients to evaluate whether 30 months of dual antiplatelet therapy results in a reduction in stent thrombosis or cardiac death or MI without an increase in bleeding compared to 12 months of dual antiplatelet therapy. This has been a truly impressive collaboration amongst DES and thienopyridine manufacturers and FDA to answer an important public health question.
I'm happy to report that study enrollment is complete, and we are now in the randomization phase in which patients who have been free of major clinical events 12 months post-stent implantation are randomized and blinded to treatment with aspirin plus a thienopyridine or aspirin plus placebo for an additional 18 months. While this study won't provide all the answers, it will certainly move us much closer to understanding optimal treatment, so that patients who receive DES and physicians who implant them will have data to guide their decision making about post-procedural medication. In addition to participating in the dual antiplatelet therapy study, DES manufacturers have continued to develop new technologies to try to address this issue.
What's on the Horizon for DES?
Dr. Farb: Ashley, what's on the horizon for DES? What should we look for in upcoming clinical trials?
Ms. Boam: Interestingly, manufacturers have focused their research and development in 2 different directions.
One school of thought is based on the premise that the best way to avoid late stent thrombosis is to effectively end up with a bare metal stent after the drug has performed its function of inhibiting restenosis. These manufacturers are working on DES in which the drug is embedded within a degradable coating. These DES would elute an antiproliferative drug over an initial period, around 30 days or so, and then over the next 6-18 months, depending on the design, the polymer coating would slowly degrade, leaving just the metal stent platform behind.
Another approach is based on the idea that after some initial period, the best stent is no stent. Instead of just involving a degradable drug polymer coating on a metallic platform, the actual stent would degrade as well. Possible advantages of a bioabsorbable stent include a reduced chronic inflammatory response following disappearance of the stent, restoration of normal arterial vasomotion, and the opportunity to perform coronary bypass surgery if needed, even if a long segment of artery was stented -- something that could be problematic if too many metal stents are placed in one artery. Studies of stents with degradable coatings and fully bioabsorbable stents are still in the early stages. No one knows which approach will be most effective at maintaining low rates of restenosis and hopefully reducing or eliminating late stent thrombosis.
Dr. Farb: Ashley, your last point is important as we consider the challenges of further innovation and improvements in DES. The currently approved devices are associated with generally low rates of adverse events, so it becomes harder for new devices to be proven superior to current products. As a result, larger clinical trials have been needed to evaluate new DES. One approach to this challenge looking forward is to design studies that enroll more complex high-risk patients, with the expectation that event rates will be higher, but to do so in a thoughtful way that would provide data that are interpretable and address the fundamental questions of safety and effectiveness.
Ms. Boam: As innovative technologies in this area continue to be developed, we look forward to working with DES manufacturers and clinical investigators to develop efficient device development programs that provide access to new safe and effective DES. This will likely mean creative approaches to permit starting early trials of promising devices and developing pivotal trials with the global community in mind. A regulatory approach that permits beneficial device innovation is a key element of the FDA's mission, but as always, Andy, the process of device evaluation requires our continued attention to patient safety.
Dr. Farb: I fully agree. This has been a great discussion. Thanks to Medscape for this opportunity and thank you for joining us today.