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 Narrator - ? 00:11 is 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. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 98 I'm your co host, Dr. Kane, and I'm Dr. Patel. Today's episode is entitled, stroke me once. Shame on you. Stroke me twice. Let's talk prevention today we're talking about secondary prophylaxis of ischemic stroke, so preventing a stroke, a second stroke after a patient has experienced a stroke already. Speaker 1 00:50 So Dr. Kane, I see these patients in my clinic, not first hand treatment, but second handed but let's get started with the case, perhaps. So our audience has an idea of what we're talking about, sure. Dr. Sean Kane 01:02 So let's say Dr. Patel that you had a patient. We'll call him SM. He's a 65 year old male presenting to your primary care clinic for routine follow up. He had a stroke about a year ago, and basically he's had complete neurologic recovery, so he has no neurologic deficits as a result of that stroke. He was basically lost a follow up during that time period, and he's non compliant. He stopped all medication, stopped all contact with health care providers. So he's basically come in one year after his stroke, saying, hey, what do I need to do to make sure I don't have that stroke again? In terms of past medical history, he knows he has hypertension, he knows he has hyperlipidemia, and obviously the ischemic stroke that happened a year ago. Social History wise. He does not drink, he does not smoke, he does not use illicit drugs. And because it's relevant for stroke, just to kind of lay it out there, we're going to assume he has no past medical history of atrial fibrillation, arrhythmias, symptoms of palpitation, nothing going down the AFib pathway, which is really relevant for stroke patients, right? Speaker 1 02:01 And then, so we are looking at the vitals for this patient. The heart rate was in the 70s. The blood pressure is 144, over 96 and we don't have the lipid panel. It's it's still pending. So what can we do to reduce his risk of having a second stroke? And so here, at this point, because he already has had a stroke, we're talking about secondary prevention. Dr. Sean Kane 02:24 Step one might be to look at some guidelines. And actually, there's a number of different relevant guidelines that are out there. And the reason that this is important is that different guidelines, obviously are published at different times, and as literature evolves, some of these guidelines are now outdated. So for example, there are 2014, American Heart Association, American Stroke Association, guidelines for the prevention of stroke and someone who's had a stroke or a TIA transient ischemic attack. But 2014 was kind of a long time ago, so we do have some other more recent guidelines as well. Speaker 1 02:53 And so in addition to the 2014 guidelines, the same association combined came up with acute ischemic stroke management guidelines in 2018 but to think about it, this is more for acute setting, which is a hospital one, Dr. Sean Kane 03:08 so this is mostly dealing with TPA and things like that, although there are some secondary prevention strategies that are initiated in the acute setting. Then finally, the 2019 atrial fibrillation guidelines produced by the AHA/ACC/HRS. You know, these do touch on AFib related stroke, but in this particular patient case, he doesn't have afib. We'll touch on that very briefly, but that's like a whole nother topic in terms of preventing strokes caused by atrial fibrillation. Speaker 1 03:37 And so with any given chronic disease. We are always talking about risk factors, right? There are some that are modifiable. There are some that are not modifiable. We have a patient presenting with some of these risk factors, and our first being hypertension. So again, looking at him in specific, he's not in the hospital, but for patients in the hospital, we let the blood pressure to be a little bit higher. This is called permissive hypertension. So they have acute stroke, we don't restrict the blood pressure to be too low, because we know the outcomes are worse for those patients. Dr. Sean Kane 04:08 And then if you look at the guidelines, they say, several days into that stroke admission for that initial stroke that a patient may have, you can start initiating the antihypertensives. In this case, we're a year out after his stroke, so we're not really going to deal with the acute management of blood pressure. Management of blood pressure, but it is important for listeners to realize that in these stroke patients on day zero, you're not aggressively managing their blood pressure. However, longer term, chronically, blood pressure is probably the most important modifiable risk factor for stroke. Speaker 1 04:38 And I mean, when we talk about modification, it's through antihypertensive. So if you look at who needs to get started on therapy, it's those with a blood pressure of greater than 140 over 90. But if you look at the patient, they have multiple risk factors. We could actually be okay with maintaining their blood pressure less than 130 over 80. We can. Dr. Sean Kane 05:00 For our example, patient, his blood pressure is 144 over 96 so that's definitely above 140 over 90 so again, this is a very important modifiable risk factor for the patient. Speaker 1 05:11 And so when we, when we talk about, you know what agent to pick? Well, the comparative evidence is pretty poor. We don't have, per se, a best regimen for secondary prevention of the stroke. But then that ties back to looking at the AHA/ACC 2017 guidelines, and looking at what are the preferred regimen agents that there are. And those are the four categories, the ACE inhibitors, the angiotensin receptor blockers, the ARBs, the thiazide diuretic, and combination of thiazide diuretic and ace inhibitor. Dr. Sean Kane 05:42 And it doesn't necessarily mean that like a calcium channel blocker, which is one of the four kind of core antihypertensives from that 2017 guideline, doesn't mean that it's worse in any way. It's just that these four drug therapies are better studied compared to other therapies out there. So step one is going to be probably picking from this list. But if this list isn't getting the job done, then of course, you potentially could be reaching for your Amlodipine or calcium channel blocker to help reach whatever target blood pressure you have for that patient. Speaker 1 06:12 And not to forget, alongside these pharmacologic agent, we need to keep some of these non Pharm therapies in mind too. Again, the AHA/ACC 2017 hypertension management guidelines do lay out these recommendations very well, but they include things such as, you know, consuming less sodium, eating more fresh fruits and vegetable aka the DASH diet, consuming less alcohol, smoking cessation, you know, increasing physical activity, etc. Dr. Sean Kane 06:39 So then the second modifiable risk factor that we're looking at is dyslipidemia. And this is almost like an inappropriate term in this context, in the sense that really, anyone who's had a stroke, regardless of what their lipid panel looks like, should be initiated on a high intensity statin. Speaker 1 06:55 And those high intensity examples are your atorvastatin (Lipitor) 80 milligrams. You could do 40 milligrams, that's that's also in that intensity, but it's less preferred, rosuvastatin (Crestor), the range is anywhere between 20 to 40 milligrams. Dr. Sean Kane 07:10 And the guidelines say, you know, if your LDL is above 100 that's the highest quality evidence for this recommendation. If your LDL is less than 100 they were actually excluded from the trial that put this on the map, called the SPARCL trial, but they still recommend it. So regardless of what your LDL is, you should be initiating high dose, high intensity statin for these stroke patients, just like you would for someone with a heart attack or other ascvd event. Speaker 1 07:34 But I will be interested in learning what this SPARCL trial is. The name is very interesting. Dr. Sean Kane 07:38 So it's a great name. So the SPARCL trial was published in 2006 in the New England Journal of Medicine. It included about 4,700 patients who had a stroke or TIA in the last one to six months. So it wasn't the absolute acute stroke period that was initiated months after a stroke, and they only looked at patients that had an LDL between 100 and 190 and if you think about it, this is why the level of evidence if your LDL is above 100 is there, because that's how the SPARCL trial was designed. Basically, they compared atorvastatin (Lipitor) 80 mg versus placebo. And the trial ran for a meeting of about five years, and the primary endpoint was, did you have another stroke? Whether you died of the stroke or not, didn't matter. Did you have another stroke? And what they found was, if you got Lipitor atorvastatin, your risk of having a recurrent stroke was 11.2% versus with placebo, 13.1% so that was roughly about a 15% reduction hazard ratio of point eight four with a significant P value with a number needed to treat over five years of 45 so every 45 patients who've had a stroke, they get Lipitor. One will not have a stroke over that five year period. So it's not nothing, but it's not extravagant benefit either. Clearly, this is not the only modifiable risk factor, as we talked about with hypertension and other kind of lifestyle modifications as well. Speaker 1 08:56 So there is a lot, many more, right? We know that having diabetes increases the risk of atherosclerosis too, aka stroke, and so everybody should be screened post stroke for diabetes. We do it with A1C testing, and when it comes to managing those hyperglycemia, we follow the ADA guidelines. But again, we're not going to go into the details. We have an episode out there to understand the 2019 ADA guidelines, but now we have those guidelines delineated based on what is their ascvd risk, right? So stroke considered as ascvd, and we should pick agents that have proven cardiovascular benefits. Dr. Sean Kane 09:33 Another modifiable risk factor is obesity, and basically you're just screening these patients based on their BMI. The guidelines recognize that modifying obesity has not directly been shown to decrease the risk of recurrent stroke, but it does change many of these other modifiable risk factors, like your blood pressure, like your lipid panel, which in turn may confer some cardiovascular benefit down the road. So it seems like a reasonable thing to do, knowing that it's actually really difficult to. Uh, manage obesity in any patient, let alone someone who just had a stroke that may have some physical activity limitations. Speaker 1 10:06 Yeah, and talking about, you know, physical activity limitations, obviously, you will need an okay from your cardiologist neurologist to say, yes, go ahead and start doing it. But if the patients are uncapable, the physical therapist can help, you know, do the evaluation and prescribed exercises. But those who are capable, you know, the recommendation on physical activity remains the same three to four times a week. About 40 minutes per session comes out to be about 150 minutes of Arabic activity per week. And we're talking about moderate to vigorous Arabic activity. You're breaking out in sweat, you know, walking, brisk, walking, jogging, et cetera. And if you Dr. Sean Kane 10:41 think about it, you know this recommendation three to four times a week for 40 minutes. It doesn't sound that much, but I would guess that most listeners who are healthy, typically probably aren't getting that much physical activity in their week anyway. So thinking about someone who has more comorbidities that may have osteoarthritis, things like that. This is a really challenging recommendation, and it's great to have a number to target, but it's also something that is likely going to be very difficult for patients to stick to for a long period of time, and Speaker 1 11:11 that's why we call this a goal. That means, you know, we don't expect our patients to get there the very next day. We have told them about the physical activity, but get them started, right? So Anything's better than nothing. Approach. They're sitting on the couch and not doing any activity. If they just walk to their mailbox to grab a mail and come back and this is, you know, twice a day, that's that's physical activity for them. But the eventual goal will be to get to that level, if at all possible, by the patient, absolutely. Dr. Sean Kane 11:39 So another risk factor that's modifiable as smoking, and it's as simple as stopping smoking, right? Again, this is something that's really hard for patients. At best, maybe one in four patients will successfully quit smoking, whereas, more realistically, it's probably closer to 10 to 15% in real life versus a randomized control trial. But patients may need smoking cessation aids. They may need patient counseling. There's things that we can offer to help stop smoking that will reduce the risk of stroke Speaker 1 12:05 down the road, and I'm going to say this based on just anecdotal data, but I feel like patients are more apt to listening about smoking cessation or even follow those recommendations after they've had a stroke, which is a little too late, but they realize that what smoking has done to them, and also realize the importance of stopping it absolutely alcohol cessation or reducing the intake, is another recommendation. So we're looking at two drinks per day limit for men and one drink per day limit for obviously non pregnant women. But if obviously, this doesn't mean that if they're not drinking, that this should, you know, encourage them to drink, but avoiding any alcohol will be great, but if they are drinking over the limit, that should be the limit that we just described. Dr. Sean Kane 12:51 And then finally, is carotid artery stenosis, and this is basically patients where their carotid arteries need to be screened to make sure that they aren't too stenosed or too narrow due to atherosclerosis, and there are specific recommendations about when to do this type of non invasive imaging, how to do the non invasive imaging, and then basically what to do with it. So roughly speaking, if any of the carotid arteries are more than 50% blocked, and definitely, if they're more than 70% blocked, these patients may be indicated for different kinds of surgeries, and we're not going to get too much into this. This is a very non drug topic, but basically what will happen is that if the decision is to do surgery, the two most common interventions is a CEA a carotid end arterectomy. This is where they essentially cut open that carotid artery, scrape out the plaque and sew you back up. An alternative to this isn't as commonly done as Cas A carotid artery stenting, and this is less invasive, where they stent open to, you know, allow more blood flow through that carotid artery. Our drug therapy won't be modified whether a patient does or doesn't have this. We're going to talk about anti platelet therapy later on in this episode. So either way, our direct therapy is going to be identical whether a patient has this or doesn't have it, but if a patient does have severe stenosis that may put them at increased risk for a recurrent stroke down the road, Speaker 1 14:10 and talking about those anti platelets and anticoagulants, that's where things get murky. We talked about modifiable risk factors, and those are all chronic disease standard of care kind of talks. But where it gets kind of muddy and gray is, you know, when do you pick aspirin? When do you pick competitor? When do you pick, you know, warfarin, or who? When do you put patient on anti thrombotic versus anti platelet? So let's, let's break that down a little bit, Dr. Sean Kane 14:35 yeah, and for sure, the simplest way to put this, and of course, there's going to be edge case, caveats and things like that. But really, the 95% of the time rule is that if you do not have atrial fibrillation, you will get an anti platelet therapy. This is going to be aspirin, Plavix, things like that. If you do have atrial fibrillation and you have an increased risk of stroke, in this case, if you've ever had a stroke that. Counts as a risk factor. So anyone with afib at higher risk will get an anticoagulant. They will not get an antiplatelet. So again, AFib anticoagulant, not AFib antiplatelet therapy. Speaker 1 15:12 And so when you talked about, you know, if they had a stroke, they get the higher risk, you know, that's, that's, they're basing it off of the risk assessment tool called Chads two vasc score Correct? Dr. Sean Kane 15:23 Yeah, yeah. So this is in patients with atrial fibrillation. We want to know what is the risk of having a stroke caused by their afib. And the Chads two vasc is a scoring system to basically come up with, what is the risk for that. And the first S in Chads two vasc is stroke. So if you've had a stroke, you get two points. And basically, if you have two points or more, you typically are going to be indicated for an anticoagulant. So really, for secondary prevention, a stroke and someone with afib, they are probably going to get an anticoagulant. Speaker 1 15:54 And I believe the guidelines are updated this year, so the chads vasc delineation is just slightly different, right? Dr. Sean Kane 16:01 Yeah, if your jazz two vasc is two or more and you're male or three or more and you're female, then you should probably receive an anticoagulant. If your jazz two vasc score is one for men or two for women, you should consider an anticoagulant. It's not a slam dunk. And if your score is zero for men or one for women, you don't do any anticoagulant at all, your risk is very low of having a stroke. Speaker 1 16:23 So having said that, I know we see commercials, and my patients ask me all the time is, what is this non valvular atrial fibrillation? Stand for, right? So let's talk about prefer anticoagulants and set the stage. What is the non valvular versus the valvular atrial fibrillation. So whenever you're looking at patient having an atrial fibrillation, so that's an abnormal pattern or rhythm of the heart we're looking at if it's caused by having either mitral stenosis or patient has mechanical heart moral placed, that's your valvular atrial fibrillation. None of the new anticoagulants are studied in that type of atrial fibrillation. So guess what the preferred anticoagulant is going to be your warfarin. Dr. Sean Kane 17:08 And this is actually a very common misconception that I think the 2019, AFib guidelines did a really, really good job of saying, Hey, this is a huge misconception. We're going to lay it out for you so everyone understands. And they basically said, you know, having a valvular problem in your heart does not mean that you have valvular afib. To your point, Dr. Patel, it's either moderate to severe mitral stenosis or a mechanical heart valve that counts as valvular afib. You can still have valvular problems and have non valvular afib. And in fact, about 20% or up to 20% of patients in these newer anticoagulant or doac trials did have some kind of valvular defect. This could be mild mitral stenosis, mitral regurge, aortic stenosis or regurge, tricuspid regurge, and sometimes even these patients had bioprosthetic valves, so not mechanical valves, but pig valves, these tissue valves. So even though they have valvular problems, they may still be put into the non valvular AFib category, and they could potentially be indicated for a doac as opposed to straight Warfarin for those valvular AFib patients. Speaker 1 18:14 So talking about, you know, valvular issues or not, another caveat that throws in a wrench into our decision between Warfarin or the new agents, is having poor renal function. And we're talking about, you know, end stage CKD, where creatinine clearance is below 15, or they are on hemodialysis. Dr. Sean Kane 18:35 Classically, this is Warfarin territory, 100% and basically the newest guidelines say, You know what, we actually don't have that much evidence for warfarin in this specific patient population. They're kind of hard to study. So they say, given that we have poor data quality, we're actually going to equally prefer Warfarin and low‑dose apixaban, the two and a half milligrams BID. And you can basically pick either of those two options, which is a little bit controversial, because we have been on the warfarin bandwagon for these renal patients for so long. So potentially, based on these new 2019 guidelines, you may see more apixaban use for better or for worse in this patient population. Speaker 1 19:11 Again, it's to remember, this is AFib patients having CKD, and so when you were talking about, you know, recurrent VTE patients and stuff, Warfarin still might be the drug of choice. Dr. Sean Kane 19:24 So basically, if you don't have valvular afib, if you don't have chronic kidney disease, or your dialysis patient, everyone else, based on the 2019 guidelines, they recommend a doac over warfarin. And that's a one a recommendation, the highest quality recommendation that you can come up with. Basically, the reason for that is that the guidelines felt based on all of the doac data for afib, again, we're not talking vte, but for afib, these guidelines felt that the doacs were at least non inferior, if not superior, in efficacy in terms of preventing strokes, and they were definitely better in reducing bleeding versus warfarin. So. An equal or maybe a little bit better efficacy, and then better safety profile, is why the DOACs are now recommended over warfarin, unless you have some of these other compelling indications. Speaker 1 20:10 And just to refresh our memory, here DOACs, we mean dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa). Dr. Sean Kane 20:23 And then another common question that comes up in my neck of the woods on the inpatient acute care setting is, you have this patient with afib who just had a stroke. Whether or not they got TPA is kind of irrelevant. The guidelines do address, when do you initiate an anticoagulant in that kind of a patient? And basically the risk is for these patients with acute stroke, the risk of hemorrhagic conversion goes up if you anticoagulate them, but the risk of having a stroke goes up if you don't anticoagulate them. So where is the happy middle ground to kind of initiate it early enough that you get benefit to prevent an early second stroke, but not so early that you increase the risk of hemorrhagic conversion. So what's that sweet spot? Dr. Kane a we don't really know for sure, but roughly speaking, for most patients, an anticoagulant, if they have AFib and just had a stroke, will be initiated within 14 days after that acute stroke. However, some patients who are at really high risk of that hemorrhagic conversion, they may wait more than that 14 days or more than two weeks period, and that's a reasonable thing to do. That patient population is basically those with very large strokes, so big infarct size, when we do a repeat head CT on those patients, or an MRI to verify that they truly had a stroke, if we start seeing a little bit of bleeding, sometimes we call it petechial bleeding, we may choose to wait beyond that two week period. Or if someone has uncontrolled hypertension, that's a huge risk factor for hemorrhagic conversion. So really, any of these patients, we may wait more than two weeks, but for a typical patient, it will be within that 14 day window. Speaker 1 21:51 So that sums up what we want to do for stroke prevention in patients who have atrial fibrillation. Let's now talk about patients who don't have atrial fibrillation. How do we prevent? What do we use as far as stroke prevention goes? Dr. Sean Kane 22:07 And we're not using anticoagulants for these patients. We're using anti platelet therapy for these patients. And typically this is going to be aspirin. So most patients will receive aspirin, and basically doses as small as 30 milligrams per day have been studied, and when we've compared something that like very low dose aspirin versus full anticoagulant with warfarin, the efficacy is not better, and that is shocking that a full dose anticoagulant like warfarin doesn't outperform low dose aspirin for this non AFib patient who just had a stroke. But it's true, and of course, the bleeding risk is higher with Warfarin or an anticoagulant versus aspirin. So for that reason, if you don't have afib, you do not get an anticoagulant, because giving that anticoagulant doesn't improve efficacy and it worsens safety, you have more bleeding. So antiplatelets are where it's at for these patients, Speaker 1 22:57 and there are many antiplatelets out there, right? So what are the common ones that we use? We have three options. We talked about aspirin. The dose ranges anywhere between 50 to 325 milligrams daily. Again, this is a class one a recommendation, Dr. Sean Kane 23:12 the next agent that is not commonly used but has an equal preference in the guidelines. A one a recommendation is aspirin with a drug called dipyridamole. The brand name of this is Aggrenox. The aspirin dose is 50 milligrams. The dipyridamole dose is 200 milligrams. We have to take it twice a day, so you're effectively getting 100 milligrams of aspirin a day. This is not commonly used because that dipyridamole causes headache GI issues like nausea and diarrhea, and it's an extended release capsule, so you can't crush it, and if someone just had a stroke, and this is the antiplatelet therapy that you want to go with, you have to have the patient have the ability to swallow. And many patients immediately after a stroke may have swallowing difficulties, and they have to get some physical therapy to kind of get their swallowing reflexes back so you can't crush it, which is another reason this isn't is not commonly used, Speaker 1 23:58 and it's bid. So if you're worried about, you know, adherence issues. Once a day aspirin versus twice a day, Aggrenox might be okay to go with the once a day regimen. Talking about another once a day regimen that we hear or see is Plavix, clopidogrel, 75 milligrams per day. However, this one garners a little bit lower evidence. We're talking about class two A, and the level of evidence is B Dr. Sean Kane 24:21 and I think that this may be a reflection of the guidelines being 2014 guidelines. Since 2014 we've had more Plavix data come out. We've even had some Brilinta (ticagrelor) data come out, and the guidelines haven't reflected that data yet. So I would expect with newer guidelines, we may see that maybe they equally prefer clopidogrel or Plavix to some of these other options as well, because clinically, that's kind of what we've done. And I think the evidence does support that to some degree. So a common question that comes up is, you initiate aspirin on a patient and they have a stroke despite giving them aspirin, what are you supposed to do in that circumstance? You know the knee jerk reaction is, well, I gave them the weak drug. The aspirin only 81 milligrams. Maybe I should give them more or something different. Dr. Patel, what do you think? Speaker 1 25:06 How about we give two pills of 325, milligram aspirin, you know, because that will do a job. Yeah. Dr. Sean Kane 25:12 And really, the guidelines are pretty specific. Here they say, you're wasting your time and probably increasing bleeding risk if you just give more aspirin dose. And you know, if you step away from the stroke field and just look at aspirin in general, we have tons of pharmacokinetic and pharmacodynamic data demonstrating that low dose is equal in anti platelet effect to higher dose of aspirin. We've definitely demonstrated this with secondary prevention of heart attacks. So basically, the guidelines say, don't change the aspirin dose and expect anything different to happen, you effectively haven't accomplished anything. Speaker 1 25:45 So what about somebody who had stroke with aspirin? Do we have any recommendations or evidence on switching the agent to a different agent? Dr. Sean Kane 25:55 So this is very common practice, and the guidelines say there's no evidence to support it, but it also doesn't seem like a bad idea, either. So basically, if you're on aspirin and you have a stroke, maybe you should think about getting Plavix or clopidogrel, or if you're on Plavix or clopidogrel, maybe you should think about switching to aspirin. There is no right answer here, just because we don't have any data, but it seems like a reasonable thing to do if you want to do it. Speaker 1 26:20 And so we have aspirin, we have the combination aspirin and dipyridamole, and we have clopidogrel. Well, let's talk about how effective these therapies are, right? So let's break it down. Dr. Sean Kane 26:31 Dr. Kane, so basically, aspirin got put on the map because of two gigantic trials called the cast trial and the IST trial. Both of these trials were 20,000 patients each. That's massive, massive. And basically, when these came out, they kind of glued them together to have a 40,000 patient kind of meta analysis, if you will. What they did was they gave either aspirin 160 milligrams a day or 300 milligrams a day. Depends on which trial you look at. Compared it to placebo. They started it within two days of having a stroke, and they continued it for two to four weeks. So actually, really not that long of a follow up period, if you think about it, basically, what they found is within that two to four week period, the risk of a second stroke happening was 1.6% with aspirin versus 2.3% with placebo. And again, this is a really short follow up period of just two to four weeks, and that number needed to treat was 142 so basically, if you initiate aspirin within 48 hours of an acute stroke and continue it for several weeks, you do have a pretty appreciable reduction in the risk of stroke, even with that within that short time period. And we've kind of extrapolated that to assume that it probably maintains that benefit over a longer period of time. Speaker 1 27:40 And so that answers our question. You know, how fast or how soon after having a stroke, we can get patients started on anti platelets, we talked about anticoagulants, we have to wait perhaps as long as 14 days to start the anticoagulation. However, for antiplatelets, in the acute ischemic stroke setting, we can start as soon as 24 to 48 hours after. You do want to wait it out if the patient was given a TPA, because the risk of bleeding is higher and definitely 24 hours after. Dr. Sean Kane 28:10 Now, when I was looking through this evidence, you know, clinically, I've relatively commonly seen dual anti platelet therapy for this patient population, where a patient has a stroke, and they're considered to be on aspirin plus Plavix, and potentially continue that lifelong as a secondary prevention strategy. Dr. Patel, do you see this in your clinic, and what is your Speaker 1 28:31 experience been? I would say, 60% of the time I see, you know, patients on combination unless they develop a GI bleed event or, you know, some sort of hemorrhagic event, and then they will be switched to only one of the agents. But unfortunately, it's still a common practice. Dr. Sean Kane 28:48 And you know, the guidelines basically say you should not do this. That would be the short answer, although there's a lot of nuance to that answer, the longer answer is, we have three different trials that have really changed practice in terms of doing it, not doing it, and unfortunately, the guidelines have not been updated enough to really reflect all of the evidence that is out there now. Speaker 1 29:11 So we have that first trial, which is the MATCH trial, that showed no efficacy benefit, but there was increased risk of bleeding, and they looked at patients with combined aspirin Plavix versus Plavix alone for duration about 3.5 Dr. Sean Kane 29:25 years in the nerdy pharmacy student, when I learned about the MATCH trial, I remembered that you shouldn't combine aspirin and Plavix because you get burned from the MATCH trial. That's a very good way to remember it. But then things got a little bit more complicated because of a publication called the chance trial. This is aspirin Plavix for 21 days, and then they continued Plavix versus just aspirin alone. So the difference here was the comparator was aspirin as opposed to Plavix, which is what we had in the MATCH trial. And this was a Trino only trial. And normally I don't get too worked up about the geography of a trial, but in this case, it actually. Might matter, and the reason it might matter is that in China, they have a lot of different epidemiologic risk factors and considerations with stroke in general, but among Asian patients, pharmacokinetics, because of genetic variations, are different. With Plavix, they're more likely to be Plavix non responders. So there's a lot of issues in terms of fully extrapolating this chance trial to a non Asian, non China population. But in the chance trial, what got people excited was that it did decrease the risk of recurrent stroke, and it did not change bleeding risk, which is a huge deal, because usually we always have this trade off, but in the chance trial, we did not observe that trade off, Speaker 1 30:39 and that's good to hear. But then we have this another trial that was more of an international trial. We called it the POINT trial, and basically it was to study Plavix and aspirin combination versus aspirin alone for 90 days. So the results showed that the combination did reduce the risk of stroke, but at the risk of increased bleeding. Dr. Sean Kane 31:00 And again, we see this trade off very commonly in acute coronary syndromes and other anti platelet therapies. So it's really not that surprising. The POINT trial was actually stopped early because they saw this increased risk of bleeding and decreased risk of stroke. So a good thing and a bad thing kind of offset both of those, Speaker 1 31:17 and the risk of major hemorrhage was point 9% with the combination therapy versus point 4% for the aspirin. This was statistically significant at the p value of 0.02, Dr. Sean Kane 31:29 so really the problem here is the point trial was very recently published. The guidelines for stroke are old. They were published in 2014 so at this point, we don't have a specific guidelines saying you should or shouldn't do this, or you should consider XYZ. So where do we go from here as clinicians that are in need of a new guideline, which is something that is not that uncommon in practice anyway, recognizing that if you're just following the guidelines, you're following guidelines that don't reflect current, best available evidence, and you you should consider that evidence. So the point trial, I think, is really important to think of. Important to think about when considering Judy combined aspirin and Plavix for secondary Speaker 1 32:07 stroke prevention. So then it would be safe to say that, you know, if aspirin is combined with Plavix, maybe we should do it for a limited duration, perhaps for the first 21 days. Dr. Sean Kane 32:17 That was reflective of how the chance trial was designed that 21 day period. And also, if you just think about how the cast and the IST trials were with aspirin, they were a two to four week duration for giving aspirin period. So I think if you're going to do it, you should probably have that limited duration of time. And you unlike with a cardiac stent, where you would continue for depending on the nature of the stent and the risk factors, months to maybe even a year or maybe longer, depending on the risk factors for the patient. Unlike that in stroke, you should really have a plan for how long you're going to continue that therapy for. It probably is not going to be months. It's going to be measured in weeks. Speaker 1 32:54 And again, that plan will be patient specific plan that would consider things such as, you know, what's the risk of long term combination therapy? And that would be evaluating the recurrent stroke risk versus the bleed risk. Dr. Sean Kane 33:08 And if you think about it, let's say you have your patient on their fourth stroke, maybe you would give them longer term aspirin plus Plavix, because you deem that they have a whatever reason, of a low hemorrhage risk, at a very, very high risk of a recurrent stroke versus another patient who likes to follow a lot, maybe you would never consider them for dual anti platelet therapy, no matter what their risk of stroke is. So very patient specific here, Speaker 1 33:31 absolutely So tying everything that we've discussed to our patient again to remember this was our 65 year old male patient had a stroke one year ago. We have complete neurologic recovery. He's not taking any of the medication because he feels great, but now he's a little worried. And the blood pressure today is 144 over 96 Dr. Sean Kane 33:50 so Dr. Patel, blood pressure is going to be our first thing to think about. I'm sure you see this all day in clinic. He's above his target blood pressure of 140 over 90 to initiate therapy. So it's time to initiate drug therapy. What would be some options and what might you pick for this patient? Speaker 1 34:04 You know, we have that thiazide, the ACE inhibitors, the ARBs, and combination thiazide and Ace looking at the blood pressure at 144 over 96 I think we can, we can get started with one agent here. I would pick either a thiazide or an ACE inhibitor in this patient. Obviously, we're waiting for the other labs to come back. Dr. Sean Kane 34:21 But absolutely, terms of his dyslipidemia, he had a stroke, based on that SPARCL trial, it's time to initiate a high dose, high potency statin. So we're probably looking at atorvastatin 80 for him, although rosuvastatin would also be a reasonable option, 20 or 40 milligrams, and it kind of doesn't depend on what his lipid panel is, no matter what his LDL is. He's indicated to get that Speaker 1 34:40 statin right? And we will use the lipid panel, however, to evaluate the efficacy of the drug. But at baseline, it doesn't really matter. The disease he has is the indication for high intensity statin, Dr. Sean Kane 34:52 and you could argue, if his LDL is 200 maybe he's going to be indicated for a PCSK9 inhibitor. So it may alter therapy down the road. But. Not today, at least Speaker 1 35:01 exactly Additionally, we will check the A1C to make sure that he doesn't have diabetes, or if so, we can initiate appropriate therapy that way. As Dr. Kane you talked about, you know, looking for another modifiable risk factor reduction would be obesity. So, you know, calculating the BMI would be important too. And then if he is completely recovered neurologically and he has enough physical strength, recommending that he initiates physical activity to reach the goal of, you know, 40 minute session, three to four times a week we're talking about aerobic activity would be appropriate. Dr. Sean Kane 35:34 So then the last thing the other drug therapy is going to be his anti platelet therapy, so he does not have afib, therefore we're not even talking about warfarin, doacs, anticoagulants. We're only talking about antiplatelet for him, the easiest one here is going to be 81 milligrams a day of aspirin, that horrible named baby aspirin. It's cheap, it's easy. That is proven to be effective in this patient population, and it would be one of the preferred therapies for secondary prevention of stroke. Speaker 1 36:00 And if he choose to go with this, you know, Aggrenox, which is the combination aspirin and dipyridamole, or Plavix (clopidogrel), are acceptable. But again, this is, you know, Aggrenox is going to be twice a day dosing, and Plavix is going to be a little bit more expensive compared to over the counter, 81 milligram aspirin. Dr. Sean Kane 36:18 And then, as we talked about dual anti platelet therapy with aspirin plus Plavix is controversial, but he's not even close to being indicated for this at this time, so that would be really in the acute setting, directly after a stroke initiated for several weeks. He's a year out. He does not need dual anti platelet therapy. He's an aspirin only kind of guy, unless he has some cardiac thing going on that would indicate him if he had a heart attack or a stent or something like that that we don't think he has based on his past medical history. So to kind of review some of the key concepts from today's episode, one key concept is modifiable risk factors. So if you look at the guidelines for stroke, they reference a ton of other guidelines, from hypertension to diabetes to obesity, things like that. So thinking about modifying those is really important for these patients. Speaker 1 37:03 And then we, you know, kind of divvy up the patient in two. So if the stroke was likely because of atrial fibrillation, we call it Cardioembolic stroke, we will start patient on anticoagulation, either with the doac or warfarin. However, we know that doacs are preferred over Warfarin in most patient by the 2019, atrial fibrillation guidelines, by ah, ACC, Dr. Sean Kane 37:25 if the patient does not have afib, or we don't suspect afib, we're going to call that a noncardioembolic stroke, meaning that we think it's probably due to atherosclerotic plaque that ruptured and caused platelets to form. And in that case, we're looking at antiplatelet therapy. This is either going to be aspirin, which is the most common aspirin, dipyridamole, which is not very commonly used, or clopidogrel, or Plavix. So any of these three options are going to be your antiplatelet therapies that you're going to pick from. Speaker 1 37:52 And in these patients who have noncardioembolic stroke, the combination of aspirin with clopidogrel is not commonly done, but if we do consider it, the duration should be smaller, maybe like 21 days, and the best evidence is in the more of the acute setting and not on the chronic setting. Dr. Sean Kane 38:09 So with that, if you want to see some references, specifically some of these guidelines, because we've kind of looked at a number of different guidelines, those guidelines are referenced at HelixTalk.com this is episode 98 we're also on Twitter at HelixTalk, if you want to see some pearls from previous episodes, or even this episode today, we love the five star reviews in iTunes, and we love hearing from our listeners. If you want to hear a topic, this is actually a topic that was requested by a listener. So if you have a topic that you'd like to hear, send us an email or a tweet or whatever, and we'll add that to our queue of potential topics coming on down the road. So with that, I'm Dr. Kane Speaker 1 38:43 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 38:47 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 Narrator - ? 38:58 to suggest an episode or contact us or 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.