Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Unknown Speaker 00:31 Welcome to HelixTalk episode 158 Dr. Khyati Patel 00:34 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is padding pad, padding your understanding of peripheral arterial disease. A brief treatment overview. Dr. Kane, I'm really excited to talk about all things peripheral arterial disease, you know, starting from definition, sort of like the staging we have, how we categorize severity of this condition, how patients present, what are the risk factors? What are some of the goals of therapy? And then guideline directed medication, therapy recommendation that are outlined by couple different guidelines that we have referenced in our show notes. Yeah. Dr. Sean Kane 01:11 And just to add to that, this was actually a listener suggested topic. So we had a listener that wanted to know more about pad and get our take on it, and we're doing the episode. So if you the listener, have any episode topics that you'd like to hear, reach out to us. You can get our contact information at HelixTalk.com, we're also on Twitter at HelixTalk. We love the suggestions, and we we do try to favor those topics when possible. Dr. Khyati Patel 01:36 All right. Dr. Kane, so laying out the land a little bit. Let's get started with the case. So we have a 67 year old white male past. Medical History is significant for hypertension, dyslipidemia and obesity. The current BMI is 41.8 also has two pack per day smoking or tobacco use history over the course of last 10 years. And patient also has obstructive sleep apnea and uses CPAP, and he's here today complaining of new onset painful cramps upon walking one to two blocks. You know, he's retired recently, and in the cold months, he's been, you know, kind of going into an indoor mall with his friends to enjoy some walk and breakfast afterwards twice a week. And he's noticed that the this pain is preventing him from walking like he used to before. And he notices that, you know, he will walk a few blocks, one to two block, and then he'll have to sit down, and then the pain kind of goes away after a few minutes. But this is something new and concerning. And so he's here today asking, you know, what can he do to treat the symptoms? Because he wants to continue this good lifestyle and enjoy, you know, the social experience with his friends. His current medications are amlodipine 10 mg daily for hypertension management, simvastatin 20 mg daily for dyslipidemia, and because he wants to manage his weight and live healthy he's also on Wegovy (semaglutide) 2.4 mg subcutaneous once a week. Dr. Sean Kane 03:08 And it looks like Dr. Patel, we did a lipid panel two months ago, so it's, you know, up to date enough that we can use it. And he has dyslipidemia. So his total cholesterol was 231 which is high, LDL, 138 which is high. HDL was 25 which is too low, and that's our good cholesterol. And the triglycerides were okay. At 148 in today's vitals, we had a blood pressure of 149 over 83 so he's hypertensive. Our rate was fine at 78 and he states his pain is a four out of 10 when he exerts himself, and has that lower extremity pain when he's walking. Dr. Khyati Patel 03:41 And with this kind of presentation, you know, we did a quick ABI, which is the Ankle-Brachial Index, and we'll talk about that in just a little bit. And that result for him was 0.85. Dr. Sean Kane 03:53 So Dr. Patel, in terms of just what is pad in general, basically, just for your vasculature and your peripheral arteries is narrowed because of plaque, atherosclerotic plaque, and that interrupts blood flow. So instead of having a fire hose to feed blood into your lower extremities, you have a garden hose. And that narrowing is caused by that plaque buildup in the arteries. Dr. Khyati Patel 04:15 And while it says peripheral arterial disease, you know, it's more common in the legs than it is in the arms. And what happens with the initial stages of pad is that is, it's kind of like a silent disease. It's asymptomatic in up to 75% of the cases. The rest of the cases could be a little bit more severe, and patient may come up with symptoms. Dr. Sean Kane 04:38 And basically, the ABI Ankle Brachial Index is how we describe the severity of the narrowing of the arteries. And this is essentially a ratio of the blood pressure in your ankle compared to the blood pressure in your brachial artery in your arm, which is where we normally check a blood pressure. And that ratio, the lower it is, it means that the flow or. Pressure to your leg is a lot lower than the flow or pressure to your arm. So anything less than 0.9 or 90% is considered abnormal, and would be in the territory of pad typically about point seven to point nine is going to be a mild abi, moderate is going to be 0.4 to 0.7 then severe is less than 40% or 0.4 meaning that the pressure in your arm is 120 the pressure in your leg would be less than 40% of 120 to give a sense of what that ABI is actually measuring. Dr. Khyati Patel 05:33 So in a you know, normal patient, Dr. Kane, this perfusion pressure, we call it, blood pressure, should be similar all throughout the body, but when you have peripheral arterial disease, you know, like you said, the garden hose, and that's why the blood's not flowing with that same pressure. And we detect lower pressure in the lower extremities. One thing to consider is our patient has symptomatic disease, where he does get cramps upon exertion. Many of these patients would have asymptomatic disease, and so the Ankle-Brachial Index is kind of the way we find out that patient has this narrowing of the arteries, Dr. Sean Kane 06:10 so in some portion of patients, so less than 20% of the time. So this is not common. They're going to have what's called intermittent claudication, or IC, and this is where they have pain, and typically in their legs when they exert themselves, and then that pain resolves when they rest. So you might have noticed that our patient is on simvastatin and amlodipine, which is actually a drug interaction that can increase the simvastatin levels. In that scenario, you might be thinking, Well, what about something like myopathies, myalgias, rhabdomyolysis, things like that. That presentation would not be consistent with exertional pain. That is going to be pain all of the time, but in this case, intermittent claudication, which is really what our patient is describing, is going to be pain when they exert and then it resolves upon rest. Dr. Khyati Patel 06:54 And if the patient does complain of atypical symptoms, they would be sort of not pain, but more like fatigue or weakness in the legs, they may describe difficulty walking or pain that is different than claudication pain. So as we said, the claudication pain is usually on exertion, feels like muscle cramps and it gets relieved, but if it's not relieved, or it continuous, or it's a sharp shooting pain, then those are kind of considered the atypical symptoms, and in worst case scenario, when there is severe interruption in the blood flow, it can lead to something called resting limb ischemia. This can present itself as resting pain, so not upon exertion, but at night. Let's say, for example, sleeping patient may complain about burning or numbness or severe restriction of blood flow, as we know, can lead to ulcerations or gangrene or non healing ulcers as well. Dr. Sean Kane 07:52 Of course, there's kinds of patients, especially with acute onset. They're typically going to be emergency surgical candidates to try to try to revascularize them very quickly. So that's obviously a very edge case compared to someone who has asymptomatic pad with an ankle brachial index that is just low. So we have a pretty good spectrum of disease here, and that's why it's important to understand kind of what stage or where on that spectrum a given patient is going to be right. Dr. Khyati Patel 08:18 And, you know, I can't help bring in what I teach in my diabetes foot exam, you know, skills lectures to kind of watch out for other skin appearance or physical appearance in the patient's leg. And this can include absent pulse, usually ABI. We go after ABI if we can't detect pedal pulses. So absent pulse is kind of like the first thing we find out patient may have kind of like almost a pale yellow, glossy, shimmery skin, cold to touch. They may say, Oh, I used to have hair on my toes, and I don't anymore, because, you know, hair growth needs nutrients, and if your blood flow is not reaching where it needs to, then you know that area is not getting the nutrients, and the hair growth also stops. And then, as I said earlier, non healing ulcers and sores, these all could be indicative of some sort of blood flow and eruptions in the periphery. Dr. Sean Kane 09:12 In terms of risk factors, you know, I think most people, given that this is an atherosclerotic disease, most people could probably come up with most of the risk factors. So we're looking at people who are older, more than 40 years of age. Race does play a role here, where black patients are a little bit more likely to have pad than non black patients, and then health conditions. So having a history of tobacco use disorder, having diabetes, having hypertension, having dyslipidemia, and then kind of interesting hyperhomocysteinemia. This is where you have an elevated level in your blood chemistry called homocysteine. If you have too much of that, that's actually associated with an increased risk of PAD. But as we'll talk about later, the treatment to fix that, which is B vitamins, has actually not been shown to be effective. So it's a risk factor, but it's effectively not a routinely targeted modifiable risk factor. Dr. Khyati Patel 10:00 Term, yeah, usually the homocystinemia, or hyper homocystinemia, has been kind of like this mysterious thing. You know, we know it may increase the risk of clotting in some patient, but really we don't go after it as a treatment either. But additionally, talking about patients, treatment goal, they kind of revolve around looking at the modifiable versus non modifiable risk factors. So, you know, out of the risk factors you mentioned, Dr. Kane, age is something that's non modifiable. Race is non modifiable. But some of these health conditions are and that's what we try to aim to improve. You know, first thing I will take a stab at is, you know, smoking cessation and the overarching goal for PAD treatment is to reduce cardiovascular complications. Often, we forget about peripheral arterial disease when we talk about coronary artery disease. My students who talk about CAD know it's ASCVD; when you mention PAD they scratch their heads. So we're putting this story straight today: PAD is an ASCVD event. So if your patient has diagnosed PAD, you would consider that patient as having atherosclerotic cardiovascular disease. Dr. Sean Kane 11:18 Then obviously, as you mentioned, Dr. Patel and someone who's had has had, let's say, a heart attack. One of our goals is to prevent future heart attacks, strokes, things like that. The same is true here. So one of our goals is to prevent or reduce future cardiovascular events. Other goals are, if they have intermittent claudication that we want to improve, that where they can walk farther without having leg pain and more severe cases, we don't want them to, you know, lose perfusion to their lower extremity and get ulcerations. Worst case would be that they have to have something like an amputation. So all of those things are goals of therapy. And then, as you mentioned, we have a lot of things where part of our goal is to reduce the modifiable risk factors. So you mentioned smoking cessation. What are some other risk factors that are modifiable that we'd like to address as part of our goals of therapy for these patients? Dr. Khyati Patel 12:09 Yeah, low hanging fruit, such as, you know, let's talk about that cigarette smoking, you know, that's been going on. Looks like it's almost a 20 year pack history here for our patient. Other things would be the health condition. So our patient does have blood pressure, and usually, proper control of the blood pressure is beneficial in patients with PAD and we're aiming to have the blood pressure lower to less than 130/80. And there is some mention in the guidelines about, you know, strategizing your ACEi/ARB therapy in patients who have PAD. We'll talk about that a little bit later too. Just with blood pressure control comes blood glucose control as well. We know that patients with diabetes have increased risk of amputation. Neuropathy is combined along with this PAD and increases the macrovascular issues in our patients. So having an A1c less than 7% has shown to reduce some of these foot-related outcomes. Dr. Sean Kane 13:09 Then, of course, from a dyslipidemia standpoint, we want these patients to be on high-intensity or maximally tolerated statin therapy. If they're overweight or obese, it'd be nice for them to lose some weight, vaccinations to prevent influenza, COVID, things like that, and then foot care. So they should be looking at their feet every day and having good behaviors related to preventing ulcerations on their feet. And then also twice a year evaluation of their feet by a healthcare provider because of peripheral arterial disease, and we already do this in patients who have diabetes, but also PAD is another patient population where a foot exam is really important. Dr. Khyati Patel 13:51 and often than not, this simple advice or patient education gets overlooked, and students, as well as pharmacists, you know, if you have good report with your patient, can be the advocate to educate patient on how to do regular foot exams at home. You know how to perform those hygienic foot behaviors at home. And then, you know, if their providers don't remember, remind the providers, hey, I'm due for my foot exam. Let's, let's get that checked Dr. Sean Kane 14:18 related to that. Dr. Patel, you know, some of those things, like weight loss, for example, can be influenced by, obviously, diet, but also exercise. And I know that exercise is one of those non pharmacologic therapies and PAD that is pretty strongly recommended. Can you kind of shine some light in terms of how much, how often, and is there truly a benefit, or is it just something that seems like a good idea? Dr. Khyati Patel 14:41 Yeah, you're right. You know, whenever we start talking about non pharmacotherapy approaches for these conditions, we talk about exercise. But I was pleasantly surprised learning more about how well exercise has been utilized and what evidence it holds for patients who have PAD. Technically, the name is structured exercise program. Think of this way. Think of this in a way where patient status, suppose MI or heart failure, has cardiac rehab, similar to that. It would be in an either an outpatient or an inpatient setting, where a patient is monitored, and they're given certain activities to improve their tolerance. Give you one example, they're asked to walk on a treadmill at certain inclination until they can tolerate that intensity, the pain, whatever max they can tolerate. And you're just basically moving that threshold of pain slowly by slowly in the structured program. The evidence for structured program that the guideline recommends is about 12 weeks in length, where patients are doing these aerobic activity for 30 to 45 minutes, three or more times per week in this structured program has been shown to be effective with patients who have intermittent claudication. So you know, it's not that there is no benefit of exercise in patients who have asymptomatic PAD, but in patients who have symptomatic PAD, the intermittent claudication pain, this structured exercise program has shown to improve walking ability, quality of life. So they were able to do certain things and activities they'd want to do. And also it kind of delays the time of onset to the intermittent claudication. So instead of, you know, them only walking one to two block, they could now walk maybe five, seven blocks before the pain comes in. And that makes a huge difference in somebody who wants to carry out, I don't know, so many daily activities, you know, walk with their grandkids, go to shopping, you know, all that stuff. Dr. Sean Kane 16:49 Dr, tell a couple things here. One, it's really important that this is a structured exercise program, as you mentioned. And the guidelines are actually pretty specific. Here they have class of recommendation, one level of evidence, A for supervised exercise program, which means essentially, almost like a personal trainer, where a patient goes to a facility and they have someone who is telling them what to do and supervising them, then they have a slightly lower class of recommendation, but still level of evidence, A for a structured community or home based exercise program where someone is kind of taking the initiative on their own and either working out with a class or kind of doing their own thing. But in all cases, the goal here is three times a week for 30 to 45 minutes. But also, in addition to the benefits that they're going to get from a PAD perspective or an intermittent claudication perspective, there's also other cardiovascular benefits and weight loss benefits and glycemic control benefits and hypertension benefits. We've seen the benefits of these lifestyle interventions in many, many different disease states. Really, even if someone doesn't have a history of PAD, they should be doing some amount of physical activity on a regular basis every single week. So this is kind of that layup shot. It is hard for patients that don't do anything, but I do think that that structured exercise program, almost that personal trainer, if you will, that's a way that you can get them to get buy in and give them confidence to be able to do this eventually on their own after they have that 12 week period. Dr. Khyati Patel 18:17 So Dr. Kane, you know, we don't really have a dietary recommendation when it comes to lifestyle modifications from this guideline. Because, as you mentioned, you know, this exercise benefits all the other conditions that the patients may have, all the other modifiable risk factors we want to attack. And it's the same story with the diet too. You know, the DASH diet, the healthy diet, all that is still going to be beneficial, because patients probably will have other conditions like dyslipidemia and obesity and stuff, but jumping into the pharmacotherapy recommendation, our guidelines that we are referring to are a couple different ones. We have them in the show note. We have the American Heart Association and American College of Cardiology guidelines. They were last published in 2016 and there was an updated statement to the guidelines made in 2021 we have both the links there and then, some of the recommendations are sort of corroborated or also nodded yes to by the CHEST physician guidelines. Although the CHEST guidelines were a little bit old. They were from 2012 Dr. Sean Kane 19:23 Dr. Patel, I know that. Actually, they really like the acronym GDMT, which is guideline directed medical therapy. What do they say about the utilization of GDMT for patients with peripheral arterial disease versus other disease states? Dr. Khyati Patel 19:39 Dr. Kane, this was the most exciting, even though, even just talking about what's recommended, they sort of put out this plea to the medical community in their 2021 statement, saying, Hey you guys, we developed this evidence based guidelines in 2016 and despite putting together that guideline, we don't see it here. Adherence to some of those guidelines, like we see adherence to immunization practices, for example. And so there are some studies done, and they found that despite having very high level of recommendation, we're talking about class I, level of evidence A, for example, putting patient on an antiplatelet therapy if they have symptomatic PAD, only 57 to like almost 60% on average, patients show adherence to that. You know, we talked earlier about how folks don't regard PAD as an atherosclerotic cardiovascular disease, and if that happens, a lot of these patients are also not on the much needed and required statin therapy. They noted about only 30-some percent with asymptomatic PAD who were on statin, and about 62% patients with symptomatic PAD were on statin. So we have a lot of treatment gaps we're seeing. And really the 2021 guidelines were just pleading like, hey, let's get this GDMT on board with our patients who have PAD Dr. Sean Kane 21:02 I think that's a great call to action to pharmacists, right so and other healthcare providers as well. But for pharmacists, this is a great role for pharmacists to identify patients who have an indication for antiplatelet, statin, smoking cessation, hypertensive management, whatever these should be addressed in these patients, because we know that they're beneficial in PAD and apparently we're not doing a great job as medical community of initiating those therapies, or at least talking to patients about those therapies. So certainly, I think that this is an important role for any healthcare provider, including pharmacists, to identify patients who need these therapies and help get those therapies started for these patients, Dr. Khyati Patel 21:42 you're absolutely right. And with that said, let's jump into what these therapies we're talking about. And the very first one, you know, if you if you saw a patient has cardiovascular disease, here in our example case, patient is smoking, you know your bells are ringing, and you're going in the right direction for antiplatelets. And so there's a couple of different agents, like our good old aspirin and clopidogrel are used; they're limited in use in those patients who have symptoms. So we're talking about intermittent claudication, or those who have asymptomatic disease but an abnormal ABI. So again, this is not for any patient. We want to always look at risk versus benefit. When we looked at antiplatelet, we also found that it helps to prevent graft occlusion and stent occlusion. We know this from CAD, but this was done in those patients who receive grafts and stents and peripheral artery disease. And so this has been shown to be beneficial, and usually we go, as I said, with aspirin or clopidogrel. So aspirin dose can be ranging from 75 to 325 mg (the staple over-the-counter dose in the United States is 81 mg). Or according to CHEST guidelines, this is again, a 2012 recommendation, 75 to 100 mg. So most likely you're going to see 81 mg aspirin used, and then clopidogrel 75 mg. And both of these are dosed daily. But when I say both of these, they're not considered dual antiplatelet therapy. So we're not adding aspirin on top of clopidogrel or clopidogrel on top of aspirin in patients who have symptomatic PAD; that's not recommended. There is no evidence for that. And we'll talk about, you know, adding antithrombotics like warfarin and DOACs, in just a little Dr. Sean Kane 23:37 bit, I think, the thought of a dual antiplatelet therapy, something that we're interested in studying more. We just don't have enough data for that. And then in terms of how long you do this for, basically, this is effectively lifelong, assuming a patient PAD doesn't magically get better. You know, anyone with PAD, assuming risks versus benefits make sense, they should be on one of these two antiplatelet therapies. A lot of the evidence for clopidogrel came from the CAPRIE trial. This was a randomized double blind trial of almost 20,000 patients, and it included patients with PAD plus other history of cardiovascular disease. And it basically compared aspirin versus Plavix, and they used the higher aspirin dose of 325 mg, and about two years of follow up, and they had this very large composite endpoint of heart attack, strokes, vascular death. And basically they showed a very small but statistically significant benefit in terms of clopidogrel versus aspirin, having a roughly like eight to 9% relative risk reduction, which is pretty small. It was basically 5.3% versus 5.8% for the composite endpoint with a number needed to treat of about 200 so slightly more efficacy with clopidogrel, but it does come along with a cost associated with that so for that reason, the guidelines don't strongly prefer one over the other, but they do say don't combine them together. Dr. Khyati Patel 24:59 So talking about combination. So the question is, what about adding warfarin, an anticoagulant on top of antiplatelet therapy? And again, the guidelines said in patients who don't have any indication for an anticoagulant like warfarin, there is no benefit of adding that in addition to aspirin, but if they do have indication for warfarin, maybe they have AFib or VTE, you're going to continue the warfarin for that indication and then continue the antiplatelet for the PAD indication. The reason for not recommending addition of warfarin-style anticoagulant is because we know the risk of bleeding, major bleeding events can outweigh the benefit here. Dr. Sean Kane 25:45 Then, of course, you know, with the new DOACs in the market, the logical question is, well, can we use, like, a lower dose of a DOAC to be able to get that balance between preventing worsening of PAD but also not increasing the risk of bleeding too much? Rivaroxaban (Xarelto) is actually FDA approved (2018) for PAD when used at a low dose of 2.5 mg BID in combination with low-dose aspirin. That indication was driven by the COMPASS and VOYAGER PAD trials. The dose here with rivaroxaban is different than the usual full treatment dose (we're using 2.5 mg twice daily) and this is always done in combination with aspirin (typically 81 mg). This was not studied with clopidogrel, and it is not triple antithrombotic therapy. Dr. Khyati Patel 26:40 So Dr. Kane the COMPASS trial included many patients with coronary disease and about 27% had PAD; it was a large, international trial that randomized patients to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg daily alone. Patients had established atherosclerotic disease or recent coronary revascularization (CABG). The population was on other secondary prevention therapies like statins (~90%), ACEi/ARBs (~71%), and beta-blockers (~70%). Dr. Sean Kane 28:52 So Dr. Patel, like the CAPRIE trial that compared aspirin versus clopidogrel, COMPASS was a mixed trial (not exclusively PAD). They looked at a composite of cardiovascular death, stroke, or MI and the rivaroxaban plus aspirin arm was superior so the trial was stopped early for efficacy. Dr. Khyati Patel 29:27 The outcome showed that the composite outcome of cardiovascular death, stroke, or MI occurred less frequently in the rivaroxaban plus aspirin group (4.1%) versus aspirin alone (5.4%): hazard ratio 0.76 (p<0.001). The number needed to treat was 77. Dr. Sean Kane 29:54 Of course, we're adding an anticoagulant, so bleeding events increased. In COMPASS rivaroxaban 2.5 mg BID plus aspirin increased major bleeding (3.1% vs 1.9% with aspirin alone); number needed to harm ~83; hazard ratio ~1.70. Dr. Khyati Patel 30:42 And this does open up a discussion of benefit versus risk, and so is your benefit here offset by the bleeding. As you notice, you know, more bleeding events happen in the combination group. And the answer is yes, you know, as described by that primary outcome. So we are always looking into that. I guess you know, the argument against this trial would be the right comparison. Would have been a dual antiplatelet group, rather than just a single comparison of aspirin 100 mg. Dr. Sean Kane 31:12 So then another trial that came up, which is more specific to PAD, is called the VOYAGER PAD trial. And this was a double blind, randomized, multi-center trial of about 6,500 patients, and all of these patients had PAD and they had some revascularization within the last 10 days. So this is a surgical procedure, or an endovascular revascularization procedure, where these patients have more severe PAD to the point where they're getting surgery to try to fix the perfusion to their lower extremity. So they randomized patients to that same combo of rivaroxaban 2.5 mg twice daily with aspirin 100 mg versus aspirin alone with a placebo. And they followed these patients for a median of 28 months. Dr. Khyati Patel 31:56 and the average patient's age, again, is very similar to our patients, 67 years old. Majority of these patients were male, white. Baseline conditions. They had hypertension, dyslipidemia, smoking. Some of these patients even had diabetes. As you know, PAD is pretty common in patients with diabetes. They also had patients who had a little bit lower eGFR so renal insufficiency, as well as those who had cardiovascular conditions like an MI or coronary artery disease. Dr. Sean Kane 32:31 And you know, as I mentioned, because these patients are having surgical procedures, you would expect them to have more severe symptoms, which they did. So almost everyone had intermittent claudication. 6% of patients had past amputations. A third had critical limb ischemia, and about a third had previous peripheral revascularizations, where this was not their first surgical procedure. So these are more advanced patients. In terms of more advanced disease, 80% of them were on statins. ACEi/ARBs was about two thirds. Almost everyone was already on aspirin, and then about half of patients were on clopidogrel, which is interesting, because statistically, that means that a good number of these patients were on dual antiplatelet therapy. But again, many of these patients had a history of CAD and may have been on DAPT for other indications. Because this was a PAD study specifically, the composite included PAD-specific endpoints such as acute limb ischemia and major amputation for vascular causes in addition to cardiovascular death, stroke or MI. Dr. Khyati Patel 34:03 And this composite was looked at by Kaplan-Meier estimates, and they found the incidence to be 17.3% in the rivaroxaban plus aspirin group versus 19.9% in the placebo group (aspirin only). Hazard ratio was 0.85 (P=0.009). Number needed to treat was 38. Dr. Sean Kane 34:34 But then, of course, we always worry about bleeding when we're adding in an anticoagulant. In VOYAGER PAD they looked at bleeding with two different definitions (TIMI and ISTH). By TIMI criteria major bleeding was 2.65% with rivaroxaban plus aspirin versus 1.87% with placebo (HR 1.43; p=0.07). By ISTH criteria major bleeding was 5.94% vs 4.06% (HR 1.42; P=0.007). Number needed to harm ~53. Dr. Khyati Patel 35:47 And again, the argument goes that comparing rivaroxaban plus aspirin to aspirin alone is one comparison; a DAPT comparator would have been informative. Overall, rivaroxaban addition should be considered case-by-case, weighing ischemic benefit versus bleeding risk. Dr. Sean Kane 36:26 And you know, Dr. Patel, at least the ACC/AHA guidelines are back in 2016 and they haven't really commented yet on the use of rivaroxaban in PAD patients; future updates will likely provide guidance. For a patient at high fall risk or with alcohol use disorder, anticoagulation may be less attractive even at low dose; for a younger patient with recurrent revascularizations and low bleeding risk, it might be reasonable. Dr. Khyati Patel 37:10 And I can't wait for more considered deliberation coming from the guidelines here, Dr. Kane. You know, we talked about the new therapy, which is Xarelto, and the evidence behind it. But there are some older therapies that are part of guideline recommendations for intermittent claudication. One is cilostazol, a reversible PDE-3 inhibitor that causes vasodilation and inhibits platelet aggregation. Dose is 100 mg twice daily (typically in addition to antiplatelet therapy). Both AHA/ACC and CHEST recommend cilostazol for patients with intermittent claudication who have not improved with supervised exercise and smoking cessation. Dr. Sean Kane 38:16 And efficacy-wise, cilostazol improves maximum and pain-free walking distance (approximately a 50% improvement from baseline) and improves quality of life measures. Safety: contraindicated in heart failure (boxed warning) due to concerns extrapolated from milrinone data. Common adverse effects include headache, diarrhea, palpitations and dizziness. In one trial about 20% of patients discontinued cilostazol by 3 months due to adverse effects. Dr. Khyati Patel 39:13 Yeah, and efficacy wise, for cilostazol, it does improve walking distance and quality of life. Everything has a trade off, and it comes with some safety concerns as discussed. Dr. Sean Kane 40:14 Thank you. The milrinone history is the reason for the heart-failure boxed warning. Milrinone increased mortality in advanced heart failure trials; cilostazol is in the same PDE-3 class so it carries a warning despite lack of direct trial evidence showing harm in heart failure patients. Dr. Khyati Patel 41:15 Well, that's pretty good to consider. Other older or unproven therapies include chelation therapy, pentoxifylline, and B-vitamin therapy for hyperhomocysteinemia; the evidence does not support routine use of these therapies for PAD. Dr. Sean Kane 41:51 And then more invasive options include revascularization — surgical bypass or percutaneous transluminal angioplasty (PTA) — for claudication that limits lifestyle and activity, typically after failing exercise and medical therapy. Dr. Khyati Patel 42:43 So that wraps our treatment discussion, and if we bring our patient case back, our patient HP is symptomatic with intermittent claudication and an ABI of 0.85 (anything <0.9 is considered PAD). He has multiple modifiable risk factors. Treatment should be holistic: address intermittent claudication and risk factor modification (smoking cessation, BP and glucose control, statin therapy, weight loss, foot care, exercise referral). Dr. Sean Kane 43:57 Then his blood pressure was high, so adding an ACEi or ARB would be reasonable; he's already on amlodipine 10 mg which is at a typical dose, but goal BP is <130/80. Dr. Khyati Patel 44:11 And Dr. Kane, thank you for pointing out that simvastatin 20 mg has an interaction with amlodipine 10 mg. More importantly though, given that PAD is ASCVD, he should be on high-intensity or maximally tolerated statin therapy (eg, atorvastatin 40–80 mg or equivalent) unless contraindicated. Dr. Sean Kane 44:53 The other thing is weight loss; his BMI is above 40 so continuing semaglutide (Wegovy) plus diet and exercise is appropriate. Dr. Khyati Patel 45:13 And a structured exercise program referral could help increase walking distance and improve symptoms. We could consider antiplatelet therapy (aspirin 81 mg or clopidogrel 75 mg daily — not both). Rivaroxaban 2.5 mg twice daily could be considered later if risk/benefit favors it. Dr. Sean Kane 45:53 And then probably not today, but if he's maximized therapy and still symptomatic or if revascularizations recur, rivaroxaban 2.5 mg BID might be considered case-by-case given bleeding risk. Dr. Khyati Patel 46:36 So our patient's plan mostly revolves around modifiable risk factors: smoking cessation, weight loss, glucose and BP control, high-intensity statin, structured exercise, and antiplatelet therapy as indicated. Dr. Sean Kane 47:06 From a pharmacotherapy standpoint, anyone with symptomatic PAD should be on aspirin 81 mg or clopidogrel 75 mg daily. For asymptomatic PAD, antiplatelet therapy should be considered depending on overall risk. Dr. Khyati Patel 47:25 Rivaroxaban 2.5 mg twice daily added to aspirin (low dose) in selected PAD patients (including after revascularization) has shown benefit in trials (COMPASS, VOYAGER PAD) but increases bleeding risk and should be chosen case-by-case. Dr. Sean Kane 48:00 Finally, for intermittent claudication, cilostazol can be considered if exercise and risk factor modification are insufficient, but avoid in heart failure. Dr. Khyati Patel 48:30 I think that wraps up today's episode quite nicely. We do have show notes at HelixTalk.com again. This is episode 158, and just another plug. This was a listener requested topic. So if you want to hear something on HelixTalk, please reach out to us through the website or through Twitter. At HelixTalk, we also have a mailing list where you can get an email whenever new episodes come out with some of the show notes from that episode, you can again subscribe to that at HelixTalk.com so with that, I'm Dr Dr. Khyati Patel 48:53 Kane and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 48:58 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there to Narrator - ? 49:09 suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.