Stroke Prevention and Therapies

Barry George: Needless to say, Fayaz, you have a bias against distal protection, and it’s an emotional issue for those of us who do carotid stenting. Fayaz Shawl: I am not biased, I just think a randomized trial is needed. Barry George: I believe that "where there’s smoke, there’s fire". I have always thought that if a distal protection device can be safely and atraumatically deployed, then it should be used. But I do agree that if the device is bumping around the lesion and can’t easily be placed, then it’s probably best not to use it. That’s just good common sense. A number of trials, such as SAPPHIRE and ARCHeR, have published their results, with SAPPHIRE being the pivotal trial. Data from the Global Carotid Artery Stent Registry [is this the proper title of the study?] were published in Catheterization and Cardiovascular Diagnosis in October 2003. The data on 12,000 patients in this registry provide a good look at the worldwide experience, as opposed to the many single-center and multicenter experiences. An analysis of the Global Carotid Artery Stent Registry data involving distal embolic protection versus no distal protection shows that the major and minor stroke rates are almost twice as common. It is also interesting to note that the data from this registry pertaining to symptomatic versus asymptomatic patients show that symptomatic patients face a greater risk of complications. The registry data are fairly positive in terms of TIAs and procedure-related and nonprocedure-related deaths. Carotid stenting is here to stay. The learning curve and experiences are extremely important in terms of arched anatomy, calcium in the carotid artery, baroreceptor response, hypertension and hypotension, and the operator had better know how to manage these complications well, because these patients have diffuse atherosclerotic disease. As for low-risk patients, there are still studies to be done. The new frontier, which I would like Jiri Vitek to address here, is in the area of intracranial interventions, particularly in acute stroke patients. I hope that we can learn from the "mistakes" we made in acute infarct interventions and apply those lessons to the cerebral bed. The cerebral bed is different, however, in terms of pathophysiology and types of arteries, and will perhaps require different mechanical and chemical reperfusion strategies. Chris Cates will now discuss the current status of the carotid stenting regulatory approval process in the U.S., as well as the type of training that physicians will receive. We don’t want people "driving without a license" once this procedure is approved by the U.S. Food and Drug Administration (FDA). Chris Cates: First of all, I think that it is very important to place everything within the proper framework. Any discussion of carotid stenting in 2004 requires mention of the pivotal SAPPHIRE trial (Stenting and Angioplasty with Protection in Patients at High RIsk for Endarterectomy), which was a high-risk patient trial, randomized to carotid surgery, with 30-day and 1-year follow-up. A concensus among the neurologists, interventional cardiologists and surgeons in terms of patient suitability for surgery was required in all three arms of the trial. In fact, SAPPHIRE was designed as a noninferiority trial, and results showed that event rates were cut in half in the carotid stent group. The ARCHeR trial (Acculink™ for Revascularization of Carotids in High-Risk patients) showed very acceptable event rates in carotid patients — and these rates were achieved despite the the fact that the surgeons turned down the majority of patients. These rejected patient were then included in a registry whose data closely mirrored those of the ARCHeR study. I am the interventional cardiology representative on the Coding and Nomenclature Committee for the American College of Cardiology (ACC). We examine most of the reimbursement issues and approve all CPT codes for cardiology. I will be discussing here the approval process, reimbursement issues — both coding and noncoverage issues from CMS — as well as training issues. Based on the ARCHeR and SAPPHIRE data, the ACC approved the CPT code in 2003. In addition, Cordis Corporation (Miami Lakes, Florida) has submitted the Pre-Market Approval (PMA) for carotid stenting based on the SAPPHIRE data that were submitted in October 2003. Cordis was granted expedited review by the FDA, with the panel date to be announced some time in April 2004. They expect approval for carotid stenting perhaps in Q-2 of this year. As for reimbursement, we went through the process several years ago with the American Medical Association (AMA)-CPT. Once the reimbursement code is approved by the ACC, it is forwarded to the AMA. The AMA felt that there were insufficient data to show the utility of the carotid stent, so it was assigned a "G" code, which is a nonreimbursed tracking code to track carotid stent usage. In order for a code to receive approval, the device in question must be widely applicable, FDA-approved, and must show efficacy in the body of evidence. Based on the fact that ARCHeR and SAPPHIRE showed such phenomenal results, the ACC moved ahead and approved the CPT code. The AMA subsequently convened a panel, for which Dr. Ken Brent and myself were the ACC representatives; we met in 3-hour conference calls over a period of six months to establish the carotid stent code. We finally created a document in Fall 2003 that was submitted to AMA-CPT committee, and we will be going next week to Puerto Rico to present that code to the AMA-CPT panel with unanimous approval of all the societies (Society of Interventional Radiology, Society of Vascular Surgeons, Society of Neurology, Interventional Neuroradiology Society, Society of Neurosurgeons, and others). The code is written to include distal protection, because the FDA will not approve a device without a system,in this case, a distal protection device and a carotid stent. Distal protection will be included in the coding weight for the RVUs, as well as a carotid angiogram on that unilateral side, cerebral and cervical carotid angiograms, all pre- and post- carotid angiograms, the carotid PTA, and the stent. We will also create one code without distal protection for patients in whom there is a failure to place a distal protection device. The AMA-CPT panel raised the issue that even though SAPPHIRE underwent expedited review, the Cordis stent was not approved. But we are moving ahead with the code because when we presented it three years ago, there was, and is now, a majority of cases in the body of evidence involving the use of an approved product in an off-label location, so we hope that that will carry the day. Just because there’s a CPT code, it doesn’t mean that the hospital will be reimbursed. At the present, the CMS has rendered a noncoverage decision regarding carotid stenting outside of a category-B IDE. Our working group drafted a sort of quid pro quo letter from all of the societies in an effort to reverse the CMS’s noncoverage decision — a rather contentious experience initially. I’d rather go to the dentist than attend some of those meetings! The ACC is waiting for the FDA to approve carotid stenting based on the ARCHeR and SAPPHIRE criteria. We do know that as a part of the carotid rollout, the FDA, and probably the CMS as well, will require a certain level of training for operators, since this is a relatively uncharted territory except for some 50–100 experienced operators in the U.S. We think that carotid stenting will require a new paradigm in training, and will likely require some sort of objective measurement of training and competence. Cordis has launched a cerebral angiography training program using simulators, which we think will probably be one of the required training steps. Cordis’s program features simulated metric-based training in a tiered approach, with carotid angiography being the first phase; once carotid angiography expertise is achieved, the operator in training would move on to carotid stenting. I anticipate that 2004 will be a very exciting year in the carotid arena. It will probably be like what I call the "perfect storm", in which everything comes together to push various specialties toward an area that had previously been inaccessible. Richard Heuser: Our institution was involved with the SAPPHIRE trial and most of the other trials. After the SAPPHIRE data were published, the surgeons were saying, "Who are these guys doing carotid endarterectomies with 12% event rates at 30 days?" But interventional cardiologists were just as bad, though we were under the illusion that our carotid stenting event rates were 1–2%; in reality, they nearly 6% at 30 days. The registry does not reflect real-world practice because some participating sites are claiming to have 1–2% event rates. The SAPPHIRE data speak for themselves and prove that a neurologist is required to independently assess patients. The FDA will hopefully approve carotid stenting in that high-risk patient population, because it is clearly a myocardial infarction-saving, stroke-saving and life-saving procedure. The one-year data are even more demonstrative of stroke reduction in terms of stenting versus surgery. But the big dilemma will be in the low-risk patient population, which represents a much larger proportion of the total patient population. The low-risk population is the subject of a much bigger controversy. Fayaz Shawl: I spoke with the FDA on this subject, and they are very interested in launching a trial, particularly in the asymptomatic population, since the majority of patients who undergo surgery are asymptomatic. The FDA would like to conduct a randomized trial that compares surgery with asymptomatic patients who have ≥ 60% angiographic stenosis. The various representatives at Cordis with whom I’ve spoken agree that this type of trial is needed. What do the panel members think about this? Chris Cates: I don’t think that the FDA will approve carotid stenting for low-risk patients. Instead, it will likely involve some iteration of high-risk patients, with criteria based on an amalgam of ARCHeR and SAPPHIRE data. The societies disagree dramatically on which patient groups they want approved for carotid stenting. Some say that carotid stenting should only be approved for symptomatic patients with a > 70% stenosis who have undergone surgical attempts on that site of the artery. I don’t think the FDA will even consider approving carotid stenting for low-risk patients until the CREST data are released. Perhaps Brian Firth can tell us more about this today. Brian Firth: There are as many agendas as there are societies involved in this issue! It has been quite difficult to work through the various agendas from the interventional neuroradiologists, neurological surgeons, vascular surgeons, and so on. Most of the people who are vociferous about SAPPHIRE have never actually looked at the data or even understood that 1) the asymptomatic patients have ≥ 80% diameter stenosed lesions, and there’s an enormous increase in stroke events in the 50–80% stenosis range; 2) the endpoints in SAPPHIRE are the most comprehensive of all the studies, so that the total event rate appears to be very high, which gets the surgeons and other professionals exercized; 3) this study featured a thorough evaluation of patients by neurologists; thus, these were not surgeons who determined that a patient had a stroke at one-month follow-up, these were neurologists who evaluated the patients within 24 hours of the procedure. Consequently, the pickup rate was higher and more accurate than what was observed in ACAS and NASCET. Having said that, the points Chris made about the CPT code were very good. The national non-coverage policy needs to be changed. We are working collaboratively with the CMS on this issue, because even if a CPT code exists, no money will flow — neither to the hospital nor to the physicians. Thus, we’ve been working assiduously on this issue for high-risk patients. For low-risk patients, both the FDA and CMS will want to see more data. Chris Cates: There has been extensive discussion within the community about the noncoverage letter that was to be sent from the ACC and a number of other societies. It was decided that the letter would not be sent because CMS didn’t want it. Brian Firth: You said Q-2; we are looking at Q-3. Jiri Vitek: I have several slides to show you. For the past two years, our institution has used distal protection in 100% of our carotid stenting patients according to the FDA-approved protocols. This slide shows the difference between results with distal protection versus no distal protection. Patient and lesion selection are extremely important factors. And as mentioned earlier, technique and pharmacological adjunctive therapy are very important as well. This next slide shows the patients treated with carotid stenting versus those who were excluded. In the past, we did not touch the asymptomatic patients who had a > 80% stenosis because those were the patients with the highest complication rates. Now that we use distal protection devices, we routinely treat these patients. There is a problem, however, with the patients who have Alzheimer’s, dementia, mitochondrial atrophy, and so on. In our experience, even if there are no neurological complications, these patients would totally disintegrate, so we don’t treat them with carotid stenting. We also excluded patients with heavy circumferential calcifications. Next, I will show slides of several of the 220 patients we stented last year, 6 of whom were excluded — 1 because of the innominate artery, 1 because of the left common carotid artery, and 4 patients because of heavy circumferential calcifications. The first image on this slide shows the patient with heavy atherosclerotic disease; the next with stenosis in the common carotid artery, in which the risk was due to access difficulties. The second image shows a tortuous common carotid artery. You may eventually succeed at getting through, but you will totally destroy the bifurcation. This next image shows the patient with the heavy circumferential calcification — this type of patient does not receive carotid stenting, but is instead referred for surgery. There is elastic recoil, you must predicate with a 2 mm balloon or 4 mm balloon, then you face the problem of passing the stent, because of the recoil factor. Again, these are patients with anatomical contraindication that render placing a distal protection device infeasible. This next slide features one of the patients we did not treat last year. This patient had heavy calcification surrounding the stenosis. This next slide shows the arctic arch. This next slide shows another patient we did not treat. This patient had heavy calcification and distal tortuosity which would have made it difficult to deploy a distal protection device. This next slide highlights the positive predictors for distal embolic protection devices which are: 1) age, especially > 80 years, 2) hypotension and hypertension. Barry George: Thank you, Jiri. Several of the slides you presented of lesions that should not be treated gave me goosebumps! Many of us have faced those same types of cases. Calcium is very evil in those situations, and we’ve learned to avoid those lesions like the plague. Mike Mooney: My experience in Minneapolis has been somewhat unique. We have three interventional neuroradiologists on staff and our carotid program has been a collaborative one from the beginning. I found, not only from clinical experience, but also from serving on the Data Safety and Monitoring Committee for the Pfizer randomized trial on stenting versus surgery, that the physicians who were known to be accomplished interventionalists, and who were thoughtful and systematic, had good patient outcomes in those early days; whereas the practitioners who had minimal experience leading in to their participation in this trial, often had poor results. I also want to say that for those of us who are tentative and think carotid stenting "isn’t our organ system", I would say that despite the fact that we traditionally have not had much experience in that area, my personal experience has shown that an accomplished interventional cardiologist is essential in most clinical settings in order to achieve good results. The interventional cardiologist’s skills, disciplines and sensibilities on how to perform a successful procedure are invaluable, and have been earned over many years of clinical experience — and these skills and experience do transfer over to the carotid arena. As for carotid endarterectomies that restenose, these patients are not good re-operation candidates and they are also not good stent candidates. I hope that industry will be able to develop appropriate-sized drug-eluting stents and/or other strategies to manage this category of patients, because gamma brachytherapy for in-stent restenosis is no longer an option. Norberto Schechtmann: I live in Florida in a growing area located near the Kennedy Space Center. We have one PCI center where approximately 2,700 interventional procedures are performed annually. I am on the other end of the spectrum because our hospital does not yet perform carotid stenting, so although I’ve followed the developments in this area over recent years, we have not yet established a program. It is interesting to listen to the discussions over the years and to see how difficult it is to implement a carotid stenting program. It would be helpful, in my view, to integrate the IAGS in order to gain better access to this technique. We know that the FDA is likely to approve carotid stenting soon. My colleagues and I are here representing my hospital in an effort to establish some sort of cooperative movement between the different disciplines, to encourage the interventional cardiologists, neurologists and vascular surgeons to work together in this field, and I am very excited to be so close to accomplishing this goal. I work extensively in peripheral intervention, though not in the carotid arteries. The carotid patients are certainly an undertreated population who would greatly benefit from carotid stenting. Hopefully, we will resolve all of these bureaucratic hurdles. A good number of doctors have been performing carotid stenting for several years now and have achieved good results. Barry George: Sorry to have to end this discussion here, but we are out of time. Thank you very much, everyone.