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Dr. Evans received his DPM from the Temple University College of Podiatric Medicine and has a BS in Pharmacy from the University of Connecticut. He is board-certified by the American Board of Foot and Ankle Surgery (Foot and Ankle) and is Chief of Podiatry at Corewell Health (Beaumont) Medical Center in Dearborn, Michigan.

He is Chair-Emeritus of the APMA Health Policy and Practice Committee and has served as a Medicare Carrier Advisory Committee (CAC) representative for over 20 years. He is active with the American Board of Foot and Ankle Surgery, having served on multiple committees including their Board of Directors for eight years, and is the immediate Past-Chair of their Communications Committee. He is the 2018 recipient of the APMA Award of Excellence and is the Podiatric representative to the PAD Guidelines Writing Committee of the American Heart Assn. and American College of Cardiology.

Dr. Evans is a nationally recognized speaker on a variety of topics including Peripheral Arterial Disease, the Diabetic Foot, Limb Salvage and Preservation, Physician Burnout, Dealing with the Difficult Patient, and Mindfulness in Medicine. Dr. Evans is in private practice in southeast Michigan.

Dr. Evans 02:38

So, the next factor just to review a little bit talks about lipids, these cholesterol analogs and triglycerides, that most of the time when you talk to your doctor, cholesterol is bad. And it's evil. And I was, you know, but effect the, the cells of your body are basically made up of cholesterol in one form or another. And you need it for a significant amount of the hormones that are formed in your body. So, cholesterol itself really not bad. It's actually a protein called Apo protein, that's, that's the problem. Cholesterol is fat soluble, so it's not can't dissolve in plasma. So, the only way I can get it into the blood and be able to be traveled out and be able to reduce release to different cells in the body is if it's attached to a protein. And these proteins are called Apo proteins. And there's a number of different types Apo Protein A, B, E, little a, they all but basically they are what the right enable the cholesterol and triglycerides to to be transferred through the blood in and we know we've got low density lipoproteins, LDLs and high density lipoproteins and high desert he really just means there's more Apo protein molecules within a holding this together as compared to the LDL. But the studies have shown that really LDL levels tend to be more toxic at times than the HDL. The problem is LDL can become HDL because they bump into each other the APL protein can either transfer cholesterol or can take it up more. So really, when we talk about cholesterol LDL, HDL, we're, we're talking about something that's not a true thing, but basically it's a way of measuring it in a blood test.

Dr. Barrett 04:52

John, let me let me interrupt you here second too, because you know, people are very versed in this good cholesterol versus bad cholesterol and, and I really don't like that because you need LDL to live as well as you need HDL. So, it seems to me that it's more how much the LDL is oxidized versus the unoxidized. So, I think the categorization of good versus bad really kind of led us down a pathway that not so accurate for people.

Dr. Evans 05:22

I totally agree. In what how I've come to think about it more is we really should be talking about the Apo protein levels, especially Apo protein B, which seems to be the major culprit in developing these atherosclerotic problems. Apo Protein A can has the opposite effect. But Apo protein B levels, tend to be more related to what we were talking about the bad cholesterol. And that's something that we really need to be watching for when we are having blood tests done to try to get the Apo protein B levels lower. And to take some of the stigma off, you know, whether it's a high density or low density, cholesterol you're looking at.

Dr. Barrett 06:08

I totally agree. Yeah, you know, and there's a big conundrum. That the research is pretty replete with studies that show if you want to have a neuro degenerative, or a neurocognitive disease, lower your cholesterol, if you're if your cholesterol is below 160, which a lot of cardiologists want to strive for that, then you're increased, you've got a greatly increased incidence of developing a neurocognitive disease like Alzheimer's or, you know, some type of other neurodegenerative process. So, you have to be a little bit careful with these absolute numbers, because we've been preached to for decades, that, Oh, that cholesterol is above 200. My God, you know. I personally want mine between 220 and 230-240, because of the neuroprotective basis, but I think it's another interesting thing. And I know you're going to touch on the thrombogenic component here in a second, which I think is really important. But there's a book that is titled as: the clot thickens, or the clot thickens by a guy named Malcolm Kendrick, and he's a fascinating writer, I believe he's, he's either a family practice or internal medicine specialist in England, who's written this great book about how the two theories of cardiovascular disease I realized we're not directly talking about PAD right now. But the two theories of cardio why somebody develops a cardiovascular disease is that it was either the cholesterol hypothesis, or it was the thrombogenic hypothesis. And the reason the thrombogenic hypothesis kind of got relegated to the background is because the discovery of statins. And so that was a multibillion-dollar thing. And so that kind of shifted the medical curriculum to go into more of the dyslipidemia camp rather than thrombogenic camp and probably in reality, it's a combination of both. I'm not smart enough to really opine on that. But I think it's interesting to talk about these different things. If you haven't seen that, I'll give you the link. And I'll put that link into the show notes because people may want to go look at that book, I highly recommend the book.

Dr. Evans 08:26

And I'm not familiar with it. So, I will definitely be reading it, because I in what my own study has leaned towards. I totally agree. We have a lot of good literature and research on the effects of lipids on certainly cardiovascular disease. And also, you know, components looking at the neurodegenerative pathologies that we run into the thrombogenic has gotten more credence more recently, because we've known that thrombin had a major effect, because people who were on warfarin Coumadin tended to have less atherosclerotic disease problems. And this was been known for 75 years. It just, we couldn't find a way to find a safe way of using that because there was such a risk of bleeding when so I guess it was safer to go once we realized the lipid effect. We've been able to identify statins and also now, PCSK9 inhibitors and others that are looking at finding ways of reducing cholesterol levels or more appropriately lipid levels.

Dr. Barrett 10:03

I was just looking at something the other day about SGLT2 inhibitors like Farxiga. And you know, and, you know, we understand the mechanism of action of the SGLT2 inhibitors pretty well, basically, it's just blocking the reuptake of glucose in your kidney and up out 95 to 100 grams of glucose a day is excreted. But it seems that that has not only long protective benefits, but cardioprotective benefits, and it's not dealing with lipids at all, it's just dealing with glucose, which I think is one of the most inflammatory molecules there is. But it's kind of interesting, as some of this research now is coming to light. I think I think the other theory that has been relegated to the back shelf, so to speak, will be talked about more.

Dr. Evans 10:51

No, I, I agree with you. I think when we're talking about situations like this, and we're just strictly looking at lipids, or thrombin, we're kind of missing the big picture, that it's a complex, that metabolic syndrome, the syndrome X has such a big effect on and the effect on the liver, with LDL and cholesterol being stored there. And the fact that there's a lot of insulin resistance that goes on here. And when that happens, the SGLT2’s are extremely important. So, it's kind of like, once, once we figure out one pathway, sooner or later we start to realize, wait a minute, there's another one that's affecting it also.

Dr. Barrett 11:41

Right, right.

Dr. Evans 11:44

Which is pretty exciting, binding all these things.

Dr. Barrett 11:47

It is. And it illustrates the point that I always try to make, and that is that humans are not nice, tidy little pathways, like we have on this slide right here. Because there's 100 other pathways that are interacting with that pathway.

Dr. Evans 12:02

You're absolutely right, you

Dr. Barrett 12:03

I mean, it makes us feel good, you know, that we can look at this pathway, and I can get a drug that blocks it at the, you know, fifth place on the schematic or something like that. But there's all these other things that are going on as well.

Dr. Evans 12:16

You're right. But you did mention something before that, really the more dangerous effect of LDL is when it becomes oxidized. And that's where we start seeing problems with it that lead to these other concerns that down the road, lead to the atherosclerotic process. And, you know, we had mentioned some different agents that can affect this. This was a recent trial that was done called the four-year trial, where they looked at PCSK9 inhibitors. And they found out that the whole idea was if we lower lipid levels or LDL levels, we've known it tends to be useful beneficial to reduce cardiovascular disease. But here it was a study that was done comparing patients who had PAD or didn't have PAD. And what the effect of this PCSK9 inhibitor was, and as you mentioned, PCSK9 inhibition works in a different pathway than what statins do. And the combination of a statin with PCSK9 is probably the most potent treatment to reduce overall lipid levels and in effect lead to better results down the road when you're trying to reduce these cardiovascular events. But this was just the results. The results of their study showing that it reduced these events. They talked about MACE major adverse cardiovascular events, and MALE major adverse limb events. Other cardiovascular events tend to be the ones that we talked with heart attack stroke, or vascular death. MALE tend to be where somebody has ischemia that requires some sort of intervention, either an amputation bypass or endovascular treatment. And if they those are major adverse limb events, you know,  they have to have a some sort of intervention or an amputation. So, MACE or MALE are often discussed when looking at this literature. And they found that both MACE or MALE was significantly reduced in patients who had this PCSK9 inhibitor which basically works on reducing lipid levels to a greater extent than just statins alone. In both patients who had PAD and those who didn't, but the ones who didn't got or who had PAD, received the greater benefit. So, this really just pointed out the importance of lipids in these disease processes. The final thing that we talked about before was thrombogenesis. And what this happens is when there is a vessel injury, that platelets are attracted to the tissue that's been injured. And these platelets actually undergo a process called activation where they change their physical nature. And in doing so, they release certain chemicals that activate different tissue, and also cause other platelets to be attracted to them. And the combination of the activated platelets mixing with red blood cells form a plug, a hemostatic plug that blocks a bleeding vessel. And so that's kind of we're looking at with how thrombogenesis develops. This slide just talks a little bit about platelets, because I thought, I didn't realize how cool they were. But actually, you know, platelets are a type of blood cell. They have no nucleus, they are only in mammals. And they're actually just extension from a blood cell called a megakaryocyte. But when they're activated, they actually change their physical appearance. And when they do it, they undergo a process called activation. Adhesion where they are able to stick together more and aggregation where they tend to have platelets clumped together. So, platelets in a non-activated form, act quite differently than those that are activated. And this is kind of an illustration of how atherosclerosis develops, we start out with that there's some sort of inflammation that will develop that can affect the endothelium that we talked about. The endothelium becomes a little bit weaker, or have slight openings. And at this point, it's just not as healthy. And it allows these LDL cells to actually come in and penetrate through the endothelium into the endothelial space inside the artery wall. And at this point, they will often become oxidized. And if they become oxidized, they attract certain other cells. And one of them is a is a blood, so called a monocyte. And a monocyte, will actually come through into the arterial through the endothelium. And at that point, they become they change structure, also, they become a macrophage. And they begin engulfing these oxidized LDL molecules. And when they do that, they're actually called a foam cell. And these foam cells are what begin to aggregate together. And they form the fatty streak that you'll often see when you're doing surgery, and you see an artery that's got these yellow streaks, and I'm anxious, these accumulation of foam cells that will develop. And as they get they clump together and become bigger, they actually formed something called an atheroma, which is just an accumulation of these in blood vessels will actually start to grow into this area trying to vascularized them from the smooth muscle. But they're really not a very healthy type of tissue. And as it gets bigger, it's this kind of lump of these foam cells connected. And sooner or later, this will get to the size that will actually begin to bulge out of the artery and we call it a fibro atheroma at that point, but it's got a fibrous cap along the top of it near where the vest lining is. And at this point, it either hardens and becomes calcified. Or the fibers cap will rupture. Now at that point in the heart, that's when we get a heart attack. This is where you get one of these atherosclerotic events that occurs. And what happens at that point is a lot of chemicals are released. The platelets realize they need to do something about this because there's a bleeding event going on. So, platelets could come through there. They team up with red blood cells, and they're held together by a chemical called fibrin and we call this a thrombus. And at this level, we have the platelets ad, and the red blood cells being held together with thrombin. So, these are two elements, platelets and thrombin are two of the chemicals that the majority of our research has led to it as far as treatment agents for heart attacks, or for peripheral arterial disease and medical treatments for this, because at this point, the event can either calcify and just further block the artery, or it can break loose go downstream. And that's where you issues of having a pulmonary embolism or a stroke, or if it goes into the legs possible occluding it in that nature. So, this is kind of just how all this stuff fits together. But our medical therapies have basically been released, or aimed at directly affecting platelets, and thrombin. I mean, along with things like blood pressure control, and diabetes and all that that's specifically for the atherosclerotic process, we look at this. And if you look at some cross sections of arteries, as they're developing this, we see that on the left, how we begin having our arteries tend to be a relatively thin nature. But as time passes, it becomes thicker, and foam cells will line it with these lipid pools. And with time, they'll develop these fibroatheromas, they may develop a fibrous cap which can rupture, and which leads to the the inflammatory process occurring, or it can just calcified.

Dr. Evans 22:01

These areas of, of atherosclerosis that develop. And we talk about this as being plaque. In certainly in the arteries, when you're doing calcium scans, or they're doing different types of imaging studies of the heart, they're looking at plaque formation. And a plaque can be either soft or hard. We talked about soft plaque as being what we're talking about here. And hard plaque is being when it becomes calcified. And there is a difference, because even though calcification is more difficult to clean out, when you're undergoing one of these endovascular procedures, a lot of times the plaque is stable, it's not going to break and go downstream, right, just narrowing the circumference of the part of the artery. Whereas soft plaque is more dangerous because it can easier break off and then cause problems downstream.

Dr. Evans 23:10

So, for the longest time, it was presented that the arteries of the body were basically the same. And the pathology that we develop within them tends to be the same too. And we have a lot of research on atherosclerotic process of the coronary arteries, a lot of research on that. And so basically, they found that there were certain ways they could reduce the risk of development of atherosclerosis or some of these major adverse cardiovascular or limb events. And it had to do primarily with research, it was done around the heart. And they found that there were certain treatments that would work well, like anti platelet therapy, we talked about an acid and aspirin therapy. Now this is part of it, or some of the other anti-platelet drugs that are used. So basically, if somebody has some sort of a coronary procedure, the probably going to be on some sort of anti-platelet therapy. And it was presumed that if it helped around the heart, that it would also be useful for the other areas of the body, in our profession, in the legs. So most of the therapies, were reusing these anti platelet therapies to reduce the risk of these major events in the legs. The problem was, we didn't get the same results. These therapies tended to work pretty good around the heart, but when we went and looked in the legs, they weren't as useful. And some studies were done just a few years ago, where they took amputations above knee amputation versus a below knee amputation. And they found that above knee amputations when they did histological evaluation of the arteries, they found that the arteries are very similar to those around the heart, where you had the typical atherosclerotic plaque that would rupture. And you have calcification of the intimal aspect of the artery, very similar to what we see in the heart. But when they went below the knee, they found that these changes occurred, a minority of the time that the majority of the lesions were chronic thrombotic occlusions and may not even had any significant traditional atherosclerotic changes. So now we're looking at that disease above the knee is more or less typical to your atherothrombotic sclerotic process that occurs around the coronary arteries. But once you get below the knee, there's a greater risk of it being thromboembolic.

Dr. Barrett 26:15

So, John has help me out here because are we talking about the stable plaque, the more calcified versus the soft plaque that's less stable? In the proximal and the above the knee?

Dr. Evans 26:28

Yes. Okay. Yes, that would be the and that the disease below the knee, or actually, let's say a proximal to the knee, it could be either it could be the, the typical atherosclerotic lesion that develops like this, they can be soft or hard plaque that would develop, but below the knee, it tended to be more of these embolic thrombotic that would break loose from something more proximal and go downstream, become lodged, and then to begin the atherosclerotic process from that.

Dr. Barrett 27:05

Okay. And yeah, there's a big distinction there.

Dr. Evans 27:09

There is, and the problem was most of the, the treatments that we had looked at the legs, and we're talking medical treatment, now not really surgical, but medical treatments, were geared towards keeping blood pressure under control, controlling diabetes, and also using anti platelet drugs. The problem is none of the anti-platelet drugs affect thrombin. Okay. And the new theory is that really to work on the disease, the further down, we get in the leg, we need to have some sort of anti-thrombotic therapy involved. Okay. So, and this, we'll talk about this in just a few minutes on this, but this was a big deal. Because we haven't been able to really find drugs that worked well against thrombin. Because they required anticoagulants and warfarin, we had found that it would significantly reduce the risk of heart attacks, stroke, if it was utilized. But there was just such a high bleeding risk, that it the mortality, morbidity from that overcame any potential beneficial effect.

Dr. Barrett 28:30

But to be clear, though, that the warfarin did have an effect distally?

Dr. Evans 28:36

Well, we really at this point, the research had had been done looking at the legs that use Warfarin was stopped. It was just the bleeding risk was too high. And even though we knew it would help the disease process, so many people would have died from bleeding out that it just wasn't safe to use. So, it's kind of like we know thrombogenesis is important, and we need to find a way of dealing with it. But it wasn't until relatively recently that we came out with drugs that were considered the direct oral anticoagulants. Eliquis and the Xarelto are these two and there's a couple others to deal with this. But, basically they work primarily on affecting thrombin. Got it? I'll talk a little bit about research in that just a minute. But I'd like to kind of move away from medical therapy for a minute and talk about somebody If that had such significant PAD that they needed to have an intervention, because we all go, you know, that's when people get severe ischemia like this or their gangrenous changes or lose them on heal, oftentimes, they have to have some sort of an intervention, you know, around the heart, we talk about it as stenting, or balloon angioplasty, or bypass where you actually take arteries, and, you know, bypass, the ones that are diseased. Well, we do it in the legs too. And right now, when we do to diagnose people with PAD, of that more serious level, we're tending to evaluate whether they need some sort of an intervention. And the techniques that have been developed, the procedures, and the technology that's available to these interventionists is amazing. Now, we'll actually go inside the artery either to route out, scrape the inside, or use lithotripsy techniques to break up clots things like this. It's just amazing what they have, they're able to do and also using stenting to someone in the legs, and they're actually being able to find some that are as useful as they are more proximately. But there's these endovascular techniques that have been developed, and they're incredible. So, the majority of our patients, yours, and my patients that have PAD, have a severity, they probably had some sort of intervention, some sort of angioplasty or a bypass right. Now, that is incredibly important, because it it affects the goal is to save the limb. And hopefully their lives that way. But the problem is the mere fact that they have an intervention for one, PAD is never fixed. Even though you may have cleaned out the inside of the artery, it's never going to be to go back to its non-atherosclerotic position, you're just basically cleaning it out. It's still going to go back up again.

Stephen Barrett  32:32

You’ve treated thesymptom, but you've done nothing for the disease process.

Dr. Evans 32:35

You're right, the disease process hasn't been affected. But you know, they've got blood flow, and with any luck, they've still got a leg to work with. So, in that regard, it's just amazing. Its life changing. But the initial disease process is still going to gonna go on, it's going to keep going really, once you have PAD, it's there until you die. Right? It just keeps getting worse. But you know, at least this way, you're staying active and you're able to do a lot of the things you would like to but the problem is that even the act of undergoing a revascularization increases your risk of having future problems. Okay? So, so one, we can never return a patient to a non -atherosclerotic state. And the majority of the research that was done, were done on patients that had coronary disease. And we just figured, well, this would also work in the legs. But more recently, we have found that's not the case. So, we're kind of looking at all this together, we're coming up with a treatment plan. All right. In fact, after somebody has a peripheral revascularization before fact that they've had an intervention increases their risk of developing one of these serious type problems, these acute limb ischemic issues from one year, and then it just increases since then. So, both the risk of having a major card adverse cardiovascular event increases, but their risk of having one of these major adverse live events, something that requires another procedure, or amputation, goes way up. So, it's like even the best treatment is still has its own risks. And why this is important to our patients and to really everyone is, even if we send somebody to have an intervention, the mere fact they have an intervention means there is a greater risk going to have problems down the road. On the on the good hand. They've got a leg on the other side for the rest of their life, the risk of these things goes up, which is extremely important for our profession. Because we need to be watchful of these patients, especially after they have an intervention. I mean, when you were I do a surgery, say we do an ankle fusion. Once it's healed, the ankles fused, right? After one of these arterial interventions, that's not the case for the rest of their life, they still have significant risk of having problems even in after a successful treatment and the best medical treatment available.

Dr. Barrett 36:03

So, let me ask you. This is kind of interesting. If the medical component was addressed more significantly, or stringently, do you think that would change these this post revascularization risk or not?

Dr. Evans 37:44

Well, yes, they will affect it. But these studies, this is almost 400,000 patients, these patients were on guideline directed medical therapy. It's not that they I mean, at least with what standard right now we're getting control of blood pressure, lipids, diabetes, those types of things. Right. So if we're doing the right things, now, there are probably other things that we can get onto now that have to do with nutritional support, or other types of lifestyle changes, that would affect let's see, even the problem is, once they have significant PAD, that requires an intervention, the risk of them having future problems goes up even greater. And that's something that we need to be aware of. I'm not saying this has got nothing against the interventionists. I mean, they're saving people's lives and lives. But the fact is, when that happens, we need to be watchful for the rest of their lives. And this is something I don't think that certainly our profession follows through with.

Dr. Barrett 39:01

I don't think our profession recognizes this fact, because the concept is they've had this unbelievable endovascular procedure, and they've got perfusion now. Okay, all's good. And it's not according to what you're showing us here.

Dr. Evans 39:17

Yes, exactly. And this was one of the things that once I started looking at this literature is like, Man, I didn't know this.

Dr. Barrett 39:26

Yeah, I mean, I think this is one of the most important take home points for the audience. Guys, just because they had a great response to their revascularisation doesn't mean they're out of the woods.

Dr. Evans 39:39

Exactly. Yeah. That's a great point. So now to go over the medical aspects of it here. We know that aspirin has been around is probably the most common drug to choose for preventing or treating these cardiovascular diseases. But, long term, the, the risk reduction hasn't been as great as we'd like. But yet, it's still very useful. And it's an important part. It's inexpensive, we understand the drug. But still, it's not the greatest for overall reducing cardiovascular disease risk. So more recently, they'd come up with a, one of the anti-platelet drugs, clopidogrel, Plavix, we're pretty much familiar with it. And most people who undergo some sort of intervention, or stent or anything like that will be on one of these anti platelet drugs or something we call dual antiplatelet therapy, which is where they have aspirin plus clopidogrel or something similar for a period of time afterwards. So, this is how we tended to treat lower extremity PAD issues. But we found it just wasn't that successful, like it was around the heart. And we talked about Warfarin as being very useful. But this bleeding risk, including intracranial hemorrhage, it just wasn't practical in, you know, in the health of our patients.

Dr. Barrett 41:18

John, let me ask you about the warfarin was there any specific INR level that they were looking at, for this? Because I mean, a higher INR is going to be much riskier than, you know, maybe something like two, two and a half versus four, right?

Dr. Evans 41:35

Yes, you're right. The problem was even having an INR between two and three, which would be considered our therapeutic areas. For most people, they still had a significant risk of hemorrhage, that can occur with minor trauma, or with dietary interventions, things like that. So, it just the risk of it. If you look at a risk benefit ratio, Warfarin has its place in certain situations, but we know bleeding risk is high. Alright, so the research has been trying to find a way that we can find drugs that have a lower bleeding risk. And that can affect ideally, both platelets and the thrombin systems. So especially for PAD, but even for cardiovascular and cerebrovascular disease, the combination of thrombin. And platelet inhibition tends to give the greatest the greatest goal of reducing these risks in patients. So that's where a lot of the research has gone trying to look at that. So, when you look at both systems, you got the coagulation cascade on the left, that we're all familiar with, but basically undergoes different chemicals that are become activated, and then they stimulate the conversion of the next level. And you know, in medicine, we all learn this. But basically, there is an extrinsic and an intrinsic pathway, they lead down to factor 10. And factor 10, when it's activated, will activate the formation of prothrombin to thrombin. And then thrombin, catalyzes fibrinogen to fibrin and fibrin is what kind of holds everything together. So, the goal was to effect on this side thrombin, because we know if we can affect thrombin, we can reduce the whole atherosclerotic development process. And that can be done through vitamin K inhibitors, which is what's the warfarin Coumadin is. But they also found that if they had drugs that would inhibit factor 10 A, from occurring, they could also block this pathway at this level. And we have a number of drugs that are available on the market now that do that. On the other side of the image, we can see where platelet activation is. And there is a number of different sites within the platelet molecule that can that have receptors that different drugs affect. And this is just talking about aspirin which affects Cox one inhibition. There's also a PPAR 1 receptor antagonist. On the other side, you look at the PPAR 2, which is where clopidogrel and that group effect. So, there's a bunch of different receptors that we have drugs the Going to effect from that side. So, for the anti-platelet drugs, we see aspirin and clopidogrel. There’re also some other ones that are quite popular, but these are affect the platelets. The problem is that none of the antiplatelet agents have activity against thrombin. So that's what we need the anticoagulant. Now, of these agents, the only one that's approved, that's gone through rigorous research to be used for peripheral arterial disease. Or even as a combination therapy has dual agents with anti-platelets is rivaroxaban. That's the only one that's got FDA approval. And it's also been the most researched factor 10 inhibitor that's out there. So, when we're talking about PAD, the idea is for medical therapy, a combination of an anti-platelet drug with, or in this case Rivaroxiban, is the only one that's on the market that's approved for this to reduce the risk of development of atherosclerotic process. And this was evaluated by a couple of major trials. One was called compass you may have heard about it, yeah, just looked about using Rivaroxiban with and without aspirin in stable cardiovascular disease, global study, almost over 27,000 patients from around the world, but it was a medical trial. And the results of that, basically came that we could reduce the risk of major adverse limb events by 46%. The need for peripheral vascular interventions by 24%. And the risk of major amputations by 67%. By using a low dose Rivaroxiban is usually given in doses of 10 to 20 milligrams, or 10 to 30 milligrams daily. This was talking about a 2.5 milligram dose twice daily, with a baby aspirin, that that's the therapeutic. The combination for that's FDA approved for use for reducing peripheral arterial disease, but also other cardiovascular diseases too. But since you know I'm talking primarily about PAD, that's what we're looking at here. So, this is significant being able to reduce the risk of amputations by 67%. Now there's a bleeding risk, there still is with this 1.6% of patients versus a point 9% For aspirin alone. So, there was no increase in fatal or symptomatic bleeding, or the more severe types of bleeding, but there still is a bleeding risk. So this type of therapy when you're losing an antiplatelet and anticoagulant bleeding is what you're concerned about. So, you got to watch for that. But this is what this study showed. There was a follow up study that was done called Voyager which use the same protocol. But the patients who were involved with this were ones who had had a revascularization. This was a surgical trial, meaning patients with undergone a successful endovascular or surgical procedure who were put on the same medications where they were taking either aspirin or aspirin and clopidogrel after the procedure versus the low dose river oxy ban plus baby aspirin, those two arms and this was the endpoint with this. Now it's kind of busy like this, but the things that that I like to think about have to do. If you look at the placebo group, we see that within three years 20% of the patients had undergone an additional procedure or had had one of these major adverse cardiovascular events. So, heart attack stroke, they either died, had an amputation or had to have another revascularization 20% This is best practice as of today. So, this is a successful surgical procedure along with best guideline directed medical therapy. So, this is 20% is the best we're looking for at all now. And they found that reducing the risk of acute limb ischemia. By using the low dose river oxy ban aspirin crews could reduce this by 33%. Now there's still a bleeding risk. But these high-risk patients who have who undergo an amputation or or revascularization primarily, the risk of them having a subsequent need for more procedures or amputation are high. And at least with this combination, at this point, we can reduce that by about 33%. It's, it's a terrible situation to be in. But the goal is to keep people alive and ideally with a limb.

Dr. Barrett 51:16

Let's talk about the bleeding risk for a second, I saw one of the well, there you go, right there, I was just kind of asked about intracranial versus a GI bleed, obviously, you know, you get a little blood in your stool, okay, that's one thing that you get a little blood in your brain, that's a totally different thing.

Dr. Evans 51:33

Totally. And when they compare the two groups, there was no increase in fatal bleeding or intracranial bleeding, or bleeding that would require readmission for another surgical procedure for that. But and you're right, the majority of the bleeding risk is GI. So, it's one of these things, you have to be aware of it, there are some patients who you wouldn't want who are at high risk of potentially having bleeding events, you wouldn't want them to undergo this type of therapy. But it's where we need to balance this for void here, they actually found that there was a six to one benefit to undergo the therapy versus not. So, six patients who were saved from having one of these later, adverse events, versus one who would have a bleed. Right? So, it's useful, but it's, it's got to be in its right place. So that's basically an overview of that we know that the current pharmacologic recommendations for this include some for people who have PAD, in our case, or have had an intervention, that they undergo anti platelet therapy of some sort, their blood pressure is brought under control, their glycemic control is imperative. And they're on some sort of lipid lowering agent statin or  PCSK 9, or there are some new agents that that don't have the same side effects, as statins do that are on the market right now. But we need to look at all this. And especially when we talk about diabetes and lipid management, it's key for controlling this process, and that we need to look at lifestyle. Hmm, smoking cessation isn't credibly important. We're finding more and more about nutritional supplements, not just a good diet, but also ways of helping to reduce the potential progression of PAD.

Stephen Barrett  53:58 What about natto kinase?

Nattokinase is as you know, I learned about it from the functional medicine guys, but it's an extremely good platelet inhibitor, and it doesn't have some of the, you know, consequences of some of the pharmacological agents that are, you know, and on the prescription side, but I think there's been one or two comparisons where they compared it to Eliquis. And it had the same anti thrombotic benefit without the complications. So, it's one of the things I have in my daily nutritional supplement carton that I take every morning. There's also some compelling interest in its neuro anti-inflammatory benefits as well.

Dr. Evans 54:56

I wasn't aware of that I have recently become I'm interested in a lot of these supplements these, what would be nutraceuticals? or non-controlled drug type? substances? And I'll have to look into that, because that's, that sounds very important.

55:45

Well, it's it works primarily by changing the,

Dr. Barrett 57:22

And you think you think a lot of the exercise benefit is due to the increase in endogenous nitric oxide production because of the mechanical action on the endothelium itself.

Dr. Evans 57:34

I think that certainly has is a major contributor to it. I mean, the increasing oxygenation of a tissue, whether it's actually a physical effect of reducing that whether it's reducing stress levels. I mean, it's got to have a multifactorial effect. But yes, I totally agree that that's got to be an important reason as to why it's beneficial. Very interesting.

Dr. Barrett 58:03

Well, that answered my two questions on those two agents, because the other thing I was going to talk about in nutrition was, you know, some of the nitrate supplementation to increase your exogenous production of nitric oxide. And that's another thing I do every day. I mean, I just, you know, supplement it, and hopefully, you know, it's helping us as we, as we age, we're making less so hopefully, we can make a little bit more to compensate that loss.

Dr. Evans 58:32

Are you right, and most of the functional cardiologists, the integrative type specialists that I've discussed this with, all of them agree with you, that really that should be part of their daily protocol are great. So anyway, in summary, it's PAD is progressive, different arterial beds can act differently, it's never fixed, requires a multifactorial approach. There's a difference between atherosclerosis and atherothrombotic nature, especially when it comes into the legs and we think about different treatment options. And it seems that dual pathway inhibition where you deal with platelets and thrombin tend to have the greatest benefit.

Dr. Barrett 59:26

That's all John, that's all you have? Come on that that was fantastic. That was wonderful.

Dr. Evans 1:01:00

Well, at present, it's pretty much you're looking at your physical signs. The ones you mentioned, are all totally online, that we look at, as to see, has the disease reached a point where it's causing some type of ischemic symptom? Right? And asking them, how about their walking habit? Are they able to how far can they walk? Do they have pain in different areas, that would be muscular, it's better joint, those types of things? Right now, besides the normal examinations that we would done, without any indication of ischemia. The Ankle Brachial Index is the most commonly used. And basically, you know, where you're checking taking blood pressure of the arm and measure that against the ankle, right? And one would be considered normal, but it's actually a span of maybe .9 to 1.3. Right?

Dr. Barrett 1:02:04

What about the toe Brachial Index?

Dr. Evans 1:02:07

Toe Brachial Index is great, it's very, very useful, because it's basically the same type of relationship ratio of the blood pressure of the arm versus that of a digit. Right. And if you're below point six, in that case, you would say there's a higher risk of that you may have PAD, it has its place, it's a little bit more difficult to perform unless you have a really tiny blood pressure cuff. And most physicians have blood pressure cuffs in their office and can easily take an arm and an ankle blood pressure, right? Or their staff can and it's very simple and inexpensive to do. But as you know, the biggest problem with the ABI, with our patient base is patients who have some degree of calcification of the arteries, either from diabetes, or from renal insufficiency, right? If you can't compress the arteries, right? That just doesn't work, because that's how you compress the artery and you see what the blood pressure is, that causes it to compress and when it opens up, right? So, toe Brachial Index is useful when the ABI is either too high or too low, but you don't trust it. Right, like a diabetic and diabetic were very well can get an ABI of 1.4. Ryan, because the medial calcinosis. Right, exactly. And you get the report back from the from wherever you sent them. And they say this is normal. It's 1.4. Well, you and I, it's not, especially if you've got some symptoms, that could be ischemic. Right. So, toe Brachial Index tends to take the place when the API is not. We don't trust it, right. The other thing that can be done are doing an API, but add exercise in. So, in which there are certain protocols you can use where you do an ABI before, and then you put them on a treadmill, you have walk or do toe raises or something like this for a period of time, and then you do an ABI again, right. And that tends to be more indicative of people who are asymptomatic or a typical or falling in a normal range where you're pretty sure that's not the case. Right? Alright. So after that, you've got the, the tissue perfusion, the TCP O2 measurements, right, which can be very, very useful. It just they're a little bit more difficult and time consuming, and they're not necessarily it depends on the temperature outside and a lot of things like this. They're just not as easy or reproducible. To use, but they can be useful. Right?

Dr. Barrett 1:05:02

Well, hopefully, hopefully in the future, we'll be able to get these inexpensive cameras. And I mean, think about how proactive that would be saving the cost, the incredible costs associated with this, not to mention the benefit of a patient's life.