IAGS 2002 Proceedings: Resolving Existing Restenosis (Part I of II)

Hall Whitworth: We have performed about 350 cases at our center and it has evolved somewhat over the last couple of years. Initially, we used the CheckMate system because of its greater length. The pullback and stepping techniques have offered significant advantages and allowed us to use the beta system’s shorter dwell times in order to increase the length, because the biggest problem was that all the lesions we treated were either longer ones or were right at the outer limit of the shorter beta system. We were somewhat reluctant to use this system until we felt comfortable with the ability to pull back and increase the treatment length. This has made a significant difference in how easy it is to use the system. The slippage of the balloon and the ability to use the cutting balloon has also made it much easier to control the injured length. In the beginning it was interesting to see the treated zone, the stented zone, the injured zone, and restenosis within the vessel and how they varied so greatly. In most cases, the solution was to have an adequate treatment length to ensure that the treatment margins on either side were sufficient. Once we could be more careful about that and extend the length well beyond the area treated — either with stepping or with a longer source — it made a big difference. With the various technologies that have come and gone over the years, it seems that the simplest ones caught on among operators of varying skill levels. Radiation has been a little more difficult for some. The appeal of these active stents is that they are easily deployed. However, the cost factor of treating all of these vulnerable plaques will come into play sooner or later. Peter Gonschior:It seems, with the advent of coated stents, that we are moving from the idea of “poor old balloon angioplasty” to “poor old stent angioplasty.” Over the past few years the improvements in anticoagulation made us spend significantly more money on treatment than we did in the past. Plavix and ReoPro cost nearly as much as the procedure itself used to cost. If you look today at covered stents and add the costs — with restenosis rates ranging from 10–50% — and if you count an average of 25%, using a covered stent in all the patients to prevent restenosis will automatically treat 75% of them. We must determine which patients are prone to restenosis and how to treat stented patients. Do we place another coated stent in those patients? Raoul Bonan: I disagree with part of what you said. Do we need to establish new indications for treating patients with coated versus non-coated stents? I think that would be very unethical. We don’t need to base our treatment decisions on cost, but rather on what is the best medical practice. The money will be found to do what’s necessary. I was Director of the Cardiac Cath Lab at Montreal Heart Institute in 1993–1994 when we received a letter from the government telling us to stop re-use. Our budget was tripled practically overnight; the Quebec government came up with the money to cover it. We started using stents in 10% of our cases and are now placing stents 100% of the time. We have a special budget for stents. Our task is to not discriminate between patients. Should you only give coated stents to very sick patients? How about your friend with the 10 mm lesion? And those patients in the middle? It is crucial for the third party payor or the government to find the money and up to the practitioners to prove that the money will be well spent. Peter Gonschior: I think the question is: Do you put a coated stent in every patient or should you just place a conventional stent and see what happens? What do you do with the “frequent flyers” — the patients who come in every 4–6 weeks with problems? Raoul Bonan: Let me show you the first slide. At least in the RAVEL study, 27% of patients without IVUS came back, while only 10% with IVUS did in TAXUS. It is not fair to those patients in the 27% category. How do we discriminate? Hall Whitworth: I agree. It would be difficult to tell a patient: “We’re putting the old stent in and if you come back, we’ll give you the new stent.” People just won’t tolerate that. If, however, a protocol could be developed to put an active stent at a certain pressure in a certain size artery, without the added cost of IVUS, I think it would be more difficult to add on some of these other expenses. It will be difficult not to put in active stents if these data ultimately are as impressive as the preliminary results indicate. Raoul Bonan: The question is: How many stents do you currently implant? In 100% of your cases? Hall Whitworth: In approximately 85% of our cases. Raoul Bonan: Why are you spending the $500? Why don’t you wait for the second pass? The balloon is very good, with an average 30–35% restenosis rate in a 10 mm lesion. With IVUS, you reduce that rate to about 10%. You have no proof that by implanting a stent in an artery with a reference diameter > 3.5, you will improve the outcome. Brian O’Murchu: Dr. Bonan, you are being provocative. On the one hand you are saying that if we use ultrasound we find all of these unapposed stents. If we use appropriate apposition in the deployment of the stents, we can significantly reduce restenosis rates. On the other hand, you are saying that once we have drug-coated stents, we should implant them in all of our patients because not doing so would be discriminatory. My question is: Should we approach this as a situation where drug-coated stents are a second-line therapy, with the first-line therapy being aggressive initial stent placement using ultrasound (CRUISE, MUSIC, etc.) and then use drug-coated stents for restenosis cases? I know that has not been looked at in any of the studies. My second question is: If you have such a low restenosis rate in these large arteries, what are you going to do? Raoul Bonan: The MUSIC trial was published in 1996 and the CRUISE trial in 2000 — but was well publicized before that. People don’t want to take the time to perform an IVUS because first of all, it is time-consuming, and second, practitioners are sometimes uncertain about how to interpret the IVUS — so that’s two strikes against it. It is so easy to implant a stent. You want to complete your case quickly and see beautiful results, with the patient leaving the cath lab and the hospital in good shape — preferably the same day. When the radial approach or closing device are used, these patients will be discharged even more quickly. You don’t want there to be any instances of acute closure. Good medical practice now would be to offer Plavix to every patient with coronary artery disease. We have enough evidence now to prescribe Plavix for life for these patients. Reginald Lowe: One of the difficulties with reserving the drug-eluting stent for the second time around is that we don’t know that it will behave in cases of in-stent restenosis like it does in de novo lesions. Jim Zidar: That is true and may be a good lead-in for Luis de la Fuente’s presentation which I loaded on my computer. He has treated approximately ten patients for in-stent restenosis. Luis de la Fuente: The first presentation on our experience with the Quanam drug delivery stent using the 7-Hexanytaxol was almost two years ago in this same IAGS meeting in Crete. At that time we presented the first 18 patients of our Registry. Our trial was begun the first week of February 1999, comprised 38 patients with 40 drug delivery stents and was stopped in May 2001. The Buenos Aires Registry with the Quanam drug delivery stent (DDS-QP2) included patients of the “real world”, for instance, six patients with acute myocardial infarction, ostial left anterior descending artery and saphenous vein grafts lesions and 9 patients with in-stent restenosis. Excluded were small vessel lesions, i.e. 12 months in 6 patients and between 6 and 12 months in the others three. The patient Nº 7 had a PTCA for a target lesion revascularization (TLR). At the present time all the patients are asymptomatic. The QCA and IVUS follow-up was performed in the 9 patients with a mean time of 9.77 months (6–26) and 1 patient had a restenosis. The initial QCA showed a minimal lumen diameter (MLD) of 0.85 ± 0.43 mm and a stenosis of 72.4 ± 8%. Post stent the MLD was 3.59 ± 0.38 and the stenosis % 2.8 ± 3.8. The acute gain was 2.40 ± 0.89 mm. At follow-up the QCA showed a MLD of 3.17 ± 0.5 mm. The stenosis was 6 ± 6.6% and the late loss was 0.08 ± 0.5 mm. The IVUS showed post stent, a mean stent diameter of 3.16 ± 0.6 mm and 3.01 ± 0.4 mm at follow-up. The post stent lumen area was 7.29 ± 2.3 mm and at follow-up was 6.87 ± 2.58 mm. The hyperplasia area was 0.9 ± 0.7 mm2; the area stenosis was 11.5% and the average neointimal thickness 0.19 ± 0.11 mm at follow-up. In a live course, we implanted a 3.0 mm diameter DDS-QP2 at 14 atm in an obese 62-year-old woman. She had in-stent restenosis of a 3.0 mm diameter stent in a proximal LAD. The IVUS showed that the 3.0 mm stent was smaller for that LAD and it was further dilated with a 3.5 mm balloon at 18 atm. The patient did well for about 7 months, when she again developed angina pectoris. A new IVUS and angiographic study was performed and the coronary angiogram showed a severe in-stent restenosis, but the IVUS disclosed that the restenosis was due to a severe recoil of the DDS-QP2, but there was no intimal proliferation. The patient was redilated with a plain balloon angioplasty. This case example highlights the importance of performing IVUS in all patients with in-stent restenosis treated with a drug delivery stent. With angiography you just see the in-stent restenosis, meanwhile the IVUS will show you if the stent is well expanded and/or there is “crushing” of the stent or intimal proliferation. This slide shows the first patient with in-stent restenosis who had a DDS-QP2 implanted in February 11,1999. At that time, she was 71 years old with aortic and mitral valve disease, with a previous stent in her LAD and two stents in the circumflex artery. The severe in-stent restenosis was in the AVE GFX stent or the circumflex artery and a 3.5 mm diameter, 18 mm length DDS-QP2 stent was deployed inside the GFX stent. The post-procedure IVUS showed that the stent was well expanded. At 6-, 14- and 26-month follow-up, you can see an excellent result and there is only minimal intimal proliferation. This patient is asymptomatic at the present time, three years later. This patient, like others in our registry with IVUS follow-up over 1 year and minimal intimal proliferation, may answer some of the questions about how long-lasting the effects might be in drug–eluting stents. In a 58-year-old male with double-vessel disease, severe obstructions in the proximal and middle third of the LAD and severe obstruction in a large latero-ventricular branch of the circumflex, we deployed a DDS-QP2, in the proximal segment and a Quanam metal stent in the middle LAD and a Velocity stent in the circumflex artery. Nine months later, the IVUS restudy showed no intimal proliferation in the DDS-QP2, severe diffuse in-stent restenosis in the Quanam bare metal stent and complete occlusion in the Velocity stent. A DDS-QP2 was implanted in the metal stent of the LAD and the Velocity was recanalized and redilated with a balloon. At present, the patient is asymptomatic. A 62-year-old male patient with a primary AMI was treated with a Jostent 3.0 mm in diameter in the proximal LAD. Five months later, the patient developed angina pectoris and a new angiographic study showed diffuse in-stent restenosis. A DDS-QP2 was implanted inside the Jostent. This patient was restudied at 22 months and the IVUS showed minimal intimal proliferation. The last case concerns a male patient who had a triple bypass surgery 24 years previously. The two bypasses to the right and circumflex arteries were occluded and he had a severe ostial and proximal lesion in the vein graft to the LAD. In 1991, we placed a Micro II AVE stent in this lesion, which restenosed at 6 months and the stent was redilated with a plain balloon. He came back with severe angina pectoris in April 2001 and a new study showed a severe diffuse in-stent restenosis in the vein graft and a drug delivery stent was implanted inside the Micro II stent. At 6-month follow-up, you can see that the angiographic study showed a good result in the vein graft. However, the IVUS showed that even though there is only minimal intimal proliferation, there is some deformity of the stent at the level of the ostium of the vein graft and the aortic wall which again illustrates the importance of the IVUS when conducting follow-up on these type of patients. I would say that drug-eluting stents have a bright future and we think that we are very close to defeating in-stent restenosis definitively. Stefan Beyar-Enke: Only a certain percentage of our patients have shown favorable results with the costly new stents. In times of decreasing resources, we are forced to be judicious with our spending because we are only reimbursed 2,000 marks for peripheral angioplasty. We cannot afford to pay $3,000 for a stent. Raoul Bonan: I think it is always relative. When the Palmaz-Schatz stent was introduced in the 1990s, it cost about $1,500. Look how much you pay for stents today in Germany: about $200–$300. I think the cost is relative to the time and the results you achieve. Though there may not be cost-savings with coated stenting, I am sure David Cohen and Rick Kuntz will provide data showing that the cost of using of coated stents is at least balanced — even at a $2,000 price tag. We cannot continue to think the way we do today about the high cost of coated stents. Rather, we need to show that if the drug performs well, it should be used routinely. Stefan Beyar-Enke: But the health insurers are not interested in these numbers. They would rather pay for a second intervention than for an expensive, albeit successful, first intervention. Raoul Bonan: But look what is now happening in the United States where you see television ads for Plavix, Vioxx, and Celebrex. When patients are educated about the superiority of one stent over another, they will insist on the superior stent. And you, as a practitioner, may encounter a lawsuit from a patient receiving an “inferior” stent causing the patient to restenose. Eberhard Zeitler: You said earlier that money is not the problem, but that we physicians must think about what is good medical practice. My responsibility is to use the best medical therapy for each patient. Medical practice is individual, it is not universal. I cannot say that all patients receive the same medical treatment. Can you tell me, for example, why 60% of your patients have no restenosis? Raoul Bonan: No, I cannot tell you why that is. Prof. Zeitler: Our scientific problem concerns why 60% of our patients develop restenosis. Coronary arteries are different than peripheral arteries. With peripheral arteries, which is my area of expertise, there are definitions: the wider coronary arteries have better long-term patency rates, while smaller arteries present a greater risk, and run-off arteries strongly influence patency. In this dimension, it is not so easy to define the peripheral run-off influence of patency in dilatation or stenting proximally. There are many variations in the coronary arteries, but in long-vessel coronary artery disease, there is less arteriosclerosis. We look at run-off and run-in and decide whether to treat the problem with stents. We place a stent to prevent complications if there is dissection, or poor results with primary dilatation, or if residual stenosis is > 20%. But if we have good primary results we cannot justify using stents because if we put all our money into stents, what resources will remain for our other patients? Thus, we need scientific proof that drug-eluting stents will prevent the need for a second intervention. If we have proof of that, then there is no question that we should routinely use them. We would only need to define in which diameters and lengths coated stents should be used. The scientific burden is to determine why some patients have no restenosis and then we can determine which patients should be treated with which stents. Raoul Bonan: I will give you a very definite answer. I think the important and only criterion in restenosis is the amount of injury you promote in the vessel. And since you cannot, even with IVUS, determine the amount of injury, you cannot foresee the amount of restenosis with that injury. I am sure that Richard Myler has something to say about this. Richard Myler: I would like to address atherosclerosis. We don’t understand the disease and the more I have learned about it, the less I seem to understand. For example, why does the internal mammary artery rarely, if ever, develop atherosclerosis? Raoul Bonan: Unless there is coarctation. Richard Myler: First of all, is it the internal elastic lamina? I don’t know. Second, atherosclerosis is a disease essentially of the human species. But restenosis — and I am delighted that you have used the terms injury and healing of an injury — is a process that occurs in all mammals. It is a process that involves the intima, the media, and the adventitia. But why the adventitia? What is the etiologic reason? In the case of lower animals — and I use the term “lower” guardedly because sometimes I wonder who is the lower animal — injury occurs in battle. The injury to the artery is on the outside of the artery in these animals. Perhaps through evolution we have gotten the adventitial response where we really don’t need it, at least in civilized men who are not in battle. Third, the notion that bigger is better was incredibly naive. If bigger meant a larger area of injury involving the media, it showed that we had no clue about the pathology involved. I think most of us would agree today that less injury is better — and it’s the same thing for stents. The stent, with its hoop strength, is taking care of this evolutionary adventitial process. But unfortunately, until now, it wasn’t doing anything for intimal hyperplasia; it might even have been encouraging it in certain cases. Genetic factors have been in evolution far longer than we have been using stents. Today we are attempting to address a wound healing process which is very genetically embedded in humans, and it will take a long time. I don’t feel discouraged if there is an occasional set-back or we are not certain where we stand, because this is a huge process. We have gotten to this point relatively quickly. I am very encouraged and I congratulate those who are involved in this work. Raoul Bonan: Richard, I want to talk about the “bigger is better” idea. I think it comes down to the notion of late-loss index to investigate the acute gain (or the injury) with the late loss. I would also like to discuss what you had to say about the adventitia because I think it interests us on two levels. First, because of the constriction; and second, for the dilatation and accommodation, and the Glacov phenomenon. All along, the adventitia accommodates the plaque until it reaches a level where it stops doing so and then plays against us. We need to understand the growth factors in the vessel that allow accommodation in the wall of all the plaque accumulation and then suddenly disappear, resulting in constriction. Any comments on this? Kirk Garratt: I do have a question, Raoul. It seems to me that we spend a lot of time pre-loading our therapies because we are not good at identifying variables that show the patient to be at high risk for late adverse events. That is why we use stents in 9 out of 10 patients instead of 3 out of 10. We don’t feel that we are very good at determining who really needs a stent at the end of an interventional procedure. But as you pointed out, we do have some data about that, and we are getting smarter in that regard. We can sometimes identify patients who are at higher risk. I would like to ask the panel if they think we are headed in the wrong direction when we talk about loading up every device, every stent, every balloon with a very powerful, toxic and probably very expensive therapy when perhaps we should spend more of our energy on becoming more skilled in our ability to identify high-risk patients. If you concur with that line of reasoning, what are your thoughts about how to proceed? (see Part II for continuation of this article)