International Circulation: The drug eluting stent was designed to attenuate the complication of in-stent restenosis but it didn’t eliminate this problem. What are the main reasons for in-stent restenosis after DES implantation?
Dr. Waksman: Yes it is true that restenosis has been significantly reduced by the use of drug eluting stents but we still see about 5% of target lesion revascularization with simple lesions and with complex lesions we see them up to 10%. It is multi-factorial; there is not one single cause. For example， it could be mechanical as we have seen some stent fractures. When the stent fractures， the polymer also fractures and the drug is released and this， in itself， can induce restenosis， usually focal restenosis. There are some biological reasons. Sometimes the drug is not effective and that is also seen in oncology that not everyone is responsive to the drugs or there is some resistance to the drugs. We also see some inflammation from the polymer. Primarily in the first generation stents， we have seen that the polymer induces neointimal inflammation and this can lead to restenosis. We are also seeing recently very late restenosis which is basically complete healing which was initially delayed but there is a price to pay for that with very late restenosis. We have seen in some of the trials， a TLR rate of 24% up to 5 years. That is pretty high when you consider 25% restenosis rate is what we used to see after 6 months， but with the drug eluting stents we can see it at 4 or 5 years.
International Circulation: So what options do we have in treating DES restenosis?
Dr. Waksman: Not many interestingly. The most practical way is to understand the mechanism because if this is a very focal restenosis and is not a stent fracture then sometimes a balloon alone would be sufficient and we don’t have to go to any major expense. The other common approach is to use another drug eluting stent. In this case you have two options: using the same type of DES or replacing it with another DES with a different class of medication perhaps. For example， if you had a TAXUS with paclitaxel， you would move to everolimus or Cypher， and vice versa. However， there is no data to support whether you should switch or use the same DES. The next option that is emerging now is the drug eluting balloon， but most of the data on the drug eluting balloon is focused on BMS restenosis not DES restenosis. In the CRT meeting just concluded， there was one presentation of a study called the Valentines Trial that did show that the drug eluting balloon is associated with a reduction in restenosis for DES but not so effective for restenosis with BMS. That study is the largest data set that we have and its numbers are limited to less than a hundred patients with 80% DES restenosis. It is really not a lot of data. I will say that in the United States， we are also using brachytherapy which is also helpful. But when you review all the options， it really doesn’t make much difference what you are doing because at the end of the day when you have restenosis of a DES， the likelihood that this will recur within a year and a half is almost 15% - no matter what you do. After that it is probably less， but we do not follow-up that many patients for such a long period of time.
International Circulation: What is your view of the latest generation of stents?
Dr. Waksman: In terms of the next generation (I don’t want to call it first， second or third)， we are seeing those with biodegradable polymer. Some of these are available in China such as BioMatrix. The polymer is biodegradable and at the end of the day you are stenting with a bare metal stent. On its own， this has not shown to reduce restenosis. Then you have the option of the complete elimination of the stent; this is the BVS program from Abbott which is not approved or available commercially anywhere in the world right now. The data is based on about 120 patients so we have to be careful， but it is very promising. We are not ever going to be free of restenosis but I have to admit that the latest generation of DES have shown acceptable results of recurrences. Five percent is acceptable as we cannot expect to reach zero restenosis rates. It is still a challenge to treat those patients. One of the issues， however， is when you look at the number of patients you see， it does not amount to many. If you lab does a thousand patients for example， 5% of these across the time span of a year is not a lot of patients in which to see that phenomenon and then to study and follow-up on. It is something we need to deal with and unfortunately at this time we have not identified a “winning” therapy right now. I think over time we will find that one therapy is better than another but for the most part， it is better to eliminate the problem at its outset by using better stent technology and also focusing on implantation because if you don’t expand a stent well， you will have restenosis. So， good stent deployment technique and selecting stents that have reported lower rates of TLR in the first place are factors that have to be taken into account and consideration when you want to eliminate this problem.
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