 For inviting me to give this presentation, actually, Dr. Kutten presents a lot of information that is very pertinent to what I'm going to be talking about, which is carotid artery disease in women. And you know, I don't think that we have been paying enough attention to this particular topic. I mean, what is this? Use this one. Oh, okay. Sorry. Okay. All right. So let's see. When Dr. Kutten asked me to give this presentation, I was a little bit, this was a big challenge, no doubt about it. And the reason for it is because, number one, I didn't want to be biased in any way since I work with Dr. Kutten. I certainly don't want her to look at me in a negative way. And I've been also married for 40 years plus, and so I have my inclinations as far as women are concerned. They're all positive, I can assure you that. But what is even more important is I tried to search literature on this particular topic and there was not much available. So I called a good friend of mine, Ann Abbott, and she's an urologist from Melbourne, Australia. And she has published close to 100 manuscripts on carotid artery disease, okay? So I said, Ann, can you help me with this particular topic? And she didn't respond for a while, and then she answered, I have nothing on it. She's a woman, she promotes treatment of carotid artery disease, identification of this, and she said, I have nothing, can we work on it together? So and you can see here from the information that she has published extensively, a lot of citations and so on. So that just tells you how frustrating this topic is and under evaluated, under diagnosed, and under treated. So as far as cerebral vascular disease is concerned, there are 16 million strokes per year occurring worldwide. And the outcomes, in a lot of instances, are dismal. Only one-third recover, one-third die, and one-third remain with significant impairment. So obviously it is extremely important, regardless of the gender, to look at this in more detail, pay attention to it, establish early diagnosis, and treat as soon as possible. Now some of the facts about incidents of carotid artery disease in women. The understanding of cerebral vascular disease in women, as I mentioned before, is hampered by paucity of studies that are dedicated to this particular topic. Actually none of the studies is dedicated to this particular topic. And the number of female patients that have been included in a variety of studies is extremely low, because most of the studies are biased towards men. And there are a variety of reasons for that. One is lack of attention, lack of diagnosis, lack of complaints, hormonal differences, and anatomical differences, and a variety of other things that we still don't know about. And there is no doubt there is a tremendous need for additional studies, paying attention to this particular problem. But there is some information that we have clearly available, that women have fewer strokes than men, as far as we know, and have a better long-term prognosis after strokes of TIA, which is a good thing. The gender differences are particularly more striking in favor of women with the age of less than 75. Once we pass that age, then obviously hormonal benefits are no longer present there. And there are other factors that play a significant role, hypertension, atherosclerosis, and so on. And as far as a number of CV risk, our concern is pretty close to equal between two genders. So that is particularly true for smokers. What is also very important is that diabetes starts rising after that age in women, and it's more prevalent in women than men after age of 75. And obviously that might also have something to do with weight gain in certain instances. Also hypertension and hyperlipidemia after the age of 75 are significantly more important than not just for women but for both genders. One thing that greatly differentiates women from men is one particular entity or condition that has nothing to do with atherosclerosis. And that's a fibromuscular dysplasia. And I'm not going to go into details, there are several types or varieties, some of it affecting more intima, some media, then you have combinations. It could be a focal disease. It could be more excessive or diffuse disease with beaded appearance. For those in layman terminology, it would look similar to let's say a peanut shell. You have septations in there. And that could lead to a variety of problems. It's very commonly seen in families. And the most common representation is in patients with renal artery stenosis causing renal vascular hypertension. But it's not only stenosis but also it can lead to aneurysm formation and dissection. So this is particularly cumbersome and concerning in patients with cerebral vascular involvement in fibromuscular dysplasia. And so this is the best that I could come up with as far as this particular entity is concerned in women. And this is from the United States registry on fibromuscular dysplasia. Now you can imagine the whole United States investigators were involved in this and they only gathered 447 patients. Obviously this is probably just the tip of the iceberg. But what you can see is renal artery is more commonly involved in any other one. But external carotid is very, very close to that as you can see. And then followed by lower extremity and then the other arteries as well. This might be a little bit difficult to read but you can see that this occurs significantly earlier than what you would see in atherosclerotic disease. And also this predominantly is a female gender pathology. And so that is certainly of great concern. Cognition strokes, TIAs are classical manifestations when you have fibromuscular dysplasia. Now fortunately enough this condition is not like atherosclerotic disease. It's relatively easily treatable with good outcomes just with plain old balloon angioplasty. You break those septations and you have very good results. Occasionally, particularly in more extensive disease and more complex involvement, you might actually cause a dissection and stenting might be indicated only in that kind of circumstances. But typically balloon angioplasty by itself is sufficient, particularly in renal vascular disease. Now of course when you have occlusion, dissection, aneurysm, then other treatments are necessary. And balloon angioplasty is not the best option. Now let's look a little bit about atherosclerotic disease of the carotid arteries in both genders. And a lot of us are focusing on what we see in coronary disease. And we try to attribute that the same thing is happening in cerebral vascular disease. We know that 95% coronary artery stenosis will very frequently cause significant symptoms and also will produce abnormal stress that's whether it's treadmill or pet or whatever else. Now with carotid artery disease, as far as the event rates are concerned, TIAs or strokes, there is no dramatic difference between 60 to 79% stenosis versus 80 to 99% stenosis. And that led to further studies that elucidated this problem a little bit further and refined the answers and we'll talk about it very shortly. But what you can see here, one of the important factor is it's not that severative stenosis is the main predictor of the event, but plaque burden. And what kind of composite you have in that plaque, whether it's liquid, whether it's fibrous, whether it's calcified, necrotic makes a big, big difference. And so what we talk about, what we talk about, coronary disease similarly so and even maybe more importantly so, vulnerable plaque is extremely important predictor in events with carotid artery disease. So let's talk a little bit about treatment. And as we know, we have surgery as an option, endoterectomy, CEA, it's commonly called, variety of techniques available, removing the plaque, performing what we call patch angioplasty, adding extra material and the aversion, atherectomy, those are the options and techniques that currently exist. And then carotid artery stenting that has been popularized for the last two decades or so and of course, medical treatment. Now as we'll see, medical treatment is becoming more and more important in the treatment of this condition. However, there are significant differences as Dr. Kutten already mentioned in peripheral vascular disease, particularly related to the lower extremities. Again, we don't have enough of women in those trials to clearly state that one particular therapy is better than the other. So interestingly enough, aspirin in previous studies didn't show to be greatly of benefit in women with symptomatic carotid stenosis, not as much as in men. And so that was certainly very disappointing. Now, ticlopidin, which was one of the earlier antiplatelet agents, also didn't show significant benefits in women. So until the so-called NASA and ECAS trials, and you can see dates, that's 1999, we did not have a clear cut evidence that surgery is of benefit regardless on the severity of stenosis in women. So in both trials, it was shown that in women presented with 70 to 80% carotid stenosis with ipsilateral moderate stroke. So now we are really reducing the number of women that would be counted for this, or with stroke or TIA, if that occurred within two to three weeks, then they benefited from CEA. There were no other benefits if they were outside of this margin of evaluation, which was kind of disappointing to a certain degree. However, that did not stop a lot of surgeons in performing carotid endoterectomy on thousands and millions actually worldwide patients that might not have been benefiting from this procedure. Now, there are other gender differences that are important as far as carotid endoterectomy of surgeries, because women were hospitalized for strokes, and those that were hospitalized for strokes had fewer endoterectomies. And again, it's not clear why. Whether they recovered faster, they didn't have symptoms, whether anatomically they were not favorable, or whether the surgeons had certain bias, gender bias for whatever reason. Not all of them were Trump supporters, so I don't know what was the main reason. Obviously, further studies are needed to elucidate those differences and implications as far as carotid endoterectomy is concerned. So obviously, carotid endoterectomy is less beneficial in women from the information that we have available than in men. Now, another thing that's very interesting, and again, we don't have the answers, but re-stenosis after carotid endoterectomy is more common in women than men. And, but important thing is that a lot of those women with re-stenosis remain asymptomatic, maybe because they're tougher or more stoic and men are more whiners, I don't know, but certainly this is a fact. So at the present time, with the latest knowledge that we have available, and what's very important when we talk about carotid artery disease, approximately 75% of patients with carotid artery disease are asymptomatic. They have no symptoms, regardless whether it's evaluated by cardiologists or by neurologists. So it means that if we don't evaluate them somehow with some other means, we're going to miss a lot of them just doing history. Physical examination is very important because if you hear a brewery, you should strongly suspect that there is significant carotid artery stenosis. So it's interesting now, I would like to mention one particular important aspect. Very few surgeons ever use stethoscopes. I have vascular surgical residents on my rotation and the patient comes with me either for routine evaluation or evaluation of carotid artery disease. And the fellow or the resident sees the patient and I ask him, what did you find? He says, nothing, the patient is asymptomatic, there's nothing wrong with him. I said, did you put a stethoscope on the carotid artery? He says, well, we are not asked to use stethoscopes. We don't know how to use stethoscopes. So they cannot diagnose the condition and this is one of the simplest ways how to establish diagnosis, whether it's a carotid disease, whether it's renal vascular with abdominal brewery, whether it's a femoral brewery and so on. So you see how important it is to do a proper evaluation. So at the present time, if you're asymptomatic, regardless of the gender, but particularly in women, the best medical therapy is the best option in asymptomatic patients with less than 70% stenosis. And you have to be able to control the risk factors, hypertension, atrial fib, smoking, cholesterol, diabetes, encourage patients to exercise, dietary restrictions, and pay attention to family history because this is extremely important. Actually, Dr. Kutten, I don't know if he mentioned clearly enough, but the incidence of abdominal aortic aneurysm is significantly higher in families. So I mean like five-fold higher than related to any other risk factors. So you have to ask about family history. Now, what's very important is transcranial Doppler is an extremely sensitive tool and indicator. And a lot of patients will have a shower of emboli or what we call hits on transcranial Doppler if you control, if you record it for the short period of time. And the patient will be asymptomatic or relatively asymptomatic, but you can identify the lesion that's vulnerable and that can predict stroke. And those patients would benefit better from carotid endoterectomy and or stenting rather than medical therapy. Because it identifies a vulnerable plaque. So we have to use this tool more frequently. So another factor that's extremely important is follow those patients closely. Because if somebody comes with a lesion that's 50% and in six months or a year after that it's 90%, this lesion is progressing very fast. Atherosclerotic calcified plaque cannot progress that fast. This is probably a vulnerable plaque that's laden with cholesterol and anachronic material. So look at the homogeneity of the echolucine plaque. Let's talk a little bit about carotid artery stenting trials. Billions of dollars have been spent worldwide on this particular issue. And there are a variety of reasons. It's amazing. I mean, there is no disease that I know where so much money and so many trials have been spent and we still don't have clear answers. Part of it is because there is a turf battle between interventionalists, cardiologists, radiologists, neuro-interventional radiologists and vascular surgeons. What is the best modality of treatment? However, when you look at all the carotid artery stenting trials and I didn't include, this is probably less than half of them. You can see that over a period of time the incidence of complications is going down dramatically. And this obviously has to do with a learning curve. Us interventionalists learning how to do this procedure properly, selecting proper patients for it, knowing who's candidate, who's not candidate. But there is also improvement in technology. No doubt about it. Because at the beginning we didn't have protection devices. Now we have a variety of protection devices. The profile of the stent is significantly lower. And we know which patient is not a good candidate. As a matter of fact, this one shows you the anatomic features that are classical, what we call a challenging arch, calcified thrombus and atheroma laden arch. It would be a contraindication or looking for trouble if you're doing procedure. All the patients, symptomatic patients within a short period of time, women, not necessarily because of gender, but because they frequently are vascular pets and have all the challenges with tortuosity, with disease arch, and smaller vessels, diffused vessels, vulnerable plaque, and so on. But as you can see on the bottom, your experience, your volume, is an extremely important factor. As you increase the number of intervention you have performed, your complication rate goes dramatically down. So let's look at some of the clinical trials and see what are the outcomes. As you can see here on the bottom, when you do carotid artery stenting, there is a high incidence of 30-day stroke, okay? Less than with carotid endoterectomy. But there is a high incidence of myocardial infarction in patients that undergo carotid endoterectomy and less with carotid stenting. And this is understandable. Most of the carotid endoterectomy procedures are being performed on the general anesthesia. General anesthesia by itself in patients with significant coronary disease has its deficiencies or problems or issues. So that is a fact. Now, this is disputable by many interventionalists and they will say, yes, there is a little bit higher incidence of stroke. But in all those trials, this was not statistically significant, which is true for some of them. And the second thing is the great majority of those strokes were minor strokes and most of the patients recovered while those patients that had myocardial infarction had a poor long-term outcomes. But when we looked at one of the more recent trials, which is a Crest trial, and this was for symptomatic and asymptomatic patients, a huge number of patients were included. However, at the end, most of the patients were asymptomatic and less the number was symptomatic. Only 35% of the patients struggle with women, again, giving you a lower number as far as information and analysis is concerned. And as you can see, periprocedural events in women were higher. And that's, again, a factor to think about when you talk about carotid artery stenting. Now, what we can see is when you look at risk benefits, carotid artery stenting versus carotid interectum, you can see that it was a little bit, therefore, less favorable for women to undergo carotid artery stenting than men. Most of the other variables were pretty close, evenly split. Now, more recently, we have had a publication in New England Journal of Medicine on so-called Act 1, which is asymptomatic trial. Huge number of patients, close to 1,500 asymptomatic patients, 62 sites in the United States, patients were randomized to stenting or carotid interectomy. Now, they were all asymptomatic. They were followed for five years and the outcomes were equal for both, carotid artery stenting versus carotid interectomy, which is amazing because this is the first trial that clearly showed that it does not matter which procedure you do regarding women and men would be of importance. Particularly for women now, for the first time we have seen that the incidence of epsilon stroke was significantly lower than in any other trials and better than with carotid interectomy. So, this is an amazing information that we have here, but obviously we don't know, we don't have all the answers, but we know that we learned how to do the procedure better. We probably scrutinized, including patients a little bit better and we treat patients medically better than we have in the past. So, this is discordant with Crest and the other trials and obviously this needs to be revalidated again in the very near future and will be. But anyhow, so one of the factors that I always think is as important or even maybe more important than randomized trials or controlled trials, particularly when they're industry driven, is to look at the real life experience. It means us that perform procedures outside of the trial because that just tells you how it's being done in a large population of patients. So, here is a review of 170 observational studies and what we can see as far as differences between carotid artery stenting and interectomy is concerned that if you are younger and you have a contralateral occlusion and you are a woman, you benefit from carotid artery stenting, but if you have some other comorbid conditions and again, that's the great majority because only 23% were in this first category, mentioned up there, then carotid interectomy is better. So, it means I'm not exactly sure that Crest, I'm sorry, that Act 1 trial is clearly validating that statement and that women benefit more from carotid artery stenting. So, there are other observational trials that have been carried on and the conclusion from those in huge number, over 5,000 patients, the carotid artery stenting and carotid interectomy among Medicare beneficiaries, Medicare, that's all above the age of 65, were comparable. So, you see a little bit of conflicting information, but regardless of what the studies show, we have to deal with the reality and the reality is that Medicare and CMS approves or disapproves certain procedure and we have to follow those guidelines, us that are involved in performing procedures on those patients. So, carotid artery stenting is only reimbursed for symptomatic patients at the present time if the stenosis is 70% or greater, which is a very, very small number of patients because as you know, 75% of patients are asymptomatic and so we have to be aware of that. That's why the number of carotid stenting is dropping dramatically. When you have symptomatic patients and stenosis is between 50% to 70% or asymptomatic, the only way how you can treat this patient with carotid artery stenting and being reimbursed if the patient is in some kind of a registry, which probably doesn't exist anymore, or clinical trial and there is only one and that's Crest 2 that's ongoing at the present time that is going to be the most extensive trial and the most costly trial, it will take 10 years. I don't know how many millions of dollars or hundreds of millions of dollars this will cost but the patients will be randomized to medical therapy, to another group will be carotid artery stenting with medical therapy and the third one will be surgery with medical therapy. And we hope that this trial will give us more answers as far as benefits are concerned. There are also newer therapies included in this trial that we didn't have during Act 1 or Crest trials and so on. So we will have some answers and they were also evaluated for vulnerable plaque which is very important and I think we'll have more answers once this trial is completed. So in summary, the understanding of cerebral vascular disease in women is hampered obviously by positive studies that are dedicated to this subgroup. And more men are included and have been included in clinical trials. So there is no doubt from all the information whether medical treatment, whether surgical treatment or carotid stenting treatment, women respond differently to our treatment than men in carotid artery disease. And obviously there is need for additional studies and some of them are forthcoming. Thank you very much for your attention.