Dr. Derek Holder provides two mini talks on reducing secondary risk after mile ischemic stroke by outlining the role of short term dual antiplatelet (DAPT) and primary care follow up.
So, our next speaker is Doctor Derek Holder, who received his medical degree from Chicago Medical School at Roseland Franklin University in Chicago, Illinois, and then completed his residency in neurology at the University of California, Davis Medical Center in Sacramento. He then completed his fellowship in vascular neurology at Washington University School of Medicine, where he's currently an associate. Professor of neurology for the Stroke and Cerebrovascular Disease program and medical director of the telestroke program. Doctor Holder sees patients at the Center for Advanced Medicine at Barnes Jewish Hospital and at the Center 40 building in Brentwood. And specializes in transient ischemic attack, hemorrhagic stroke, cerebral, amyloid, angopathy, telesstroke, regional stroke care, triage, hyper acute management of stroke, and chronic mood change after a stroke. So basically a lot of stroke. So, thank you so much, Doctor Holder, for your time today. We really appreciate it. Um, usually, everybody's gonna give your talk, everybody's gonna be putting uh The questions in the Q&A and chat, and we'll get to those at the end of the program. Thank you, Nikki. I'm giving a talk today about reducing secondary risk after mild ischemic stroke or TIA transient ischemic attack, and also the role of short term um follow up with primary care. Um, so two kind of mini talks at once. The first dealing with short term dual antiplatelet, and the second is um the importance of following up with your um. You alls group with primary care, and both of these can certainly reduce the risk of secondary stroke. Um, I have no disclosures, make sure my slides are advancing correctly here. I have no disclosures. I am a full-time stroke neurologist, um, in the clinical world and so certainly if there's any questions about clinical stroke care, I'm happy to answer those. So today's objectives, I want to talk about the scope and role of short-term dual antiplatelet or das for up to 30 days after a mild stroke or TIA as well as the importance of reducing hemorrhagic complications with daps by discontinuing between 21 and 30 days. Uh, as well as reviewing the AHA, American Heart Association, American Stroke Association guidelines for secondary ischemic stroke prevention with specific regards to blood pressure, blood pressure control, uh, blood cholesterol, statin, and antiplatelet therapies, a lot of which is part of the transition of care visits and further follow up with both primary care as well as the neurology clinic. So as you all know, stroke is very common. It's about 800,000 American patients per year, many of which have already had a stroke in the past. Uh, we're gonna be talking mostly about ischemic stroke today, which is 87% of the strokes, um, so, you know, close to 9 in 10 of those are, uh. Ischemic strokes, which are usually due to blood clots either from a thromboembolism, um, from a clots upstream in a blood vessel like in the neck, the carotid arteries, um, or potentially uh a cardio embolism from the heart, um, or other small vessels along the way and then uh 13% of those are hemorrhagic strokes. Again, we're gonna be mostly talking about preventing ischemic strokes today. Why we care so much about the use of short-term danti platelet is uh the science basis, as well as the American Heart Association, American Stroke Association uh guideline from 2019, which was updated to be a level one a recommendation for short-term use of dual antiplatelet for patients with minor non-cardiombolic ischemic stroke. And that has um evolved in clinical practice to involve TIAs as well based on the same evidence which we'll talk about here. So the evidence here goes back over a decade at this point, uh, to a few different trials which we'll talk about briefly and then we'll talk about uh logistics um as well, but aspirin uh was compared to a combination of aspirin and clopidogrel or Plavix back in 2013 in the CAS trial, which used 21 days of dual antiplatelet after a mild stroke or TIA. The idea was to start this in the clinical trial within 24 hours of the events. Uh, patients needed to have high risk features of the TIA, so, um, essentially things like high blood pressure, um, weakness, or speech changes with that, uh, diabetes or long duration can help with adding up the risk of ATI. through the ABCD 2 score if you're not familiar with that, um, where they had to have a low stroke scale, meaning uh NAH stroke scale of less than 4, so 0 through 3 indicating a mild stroke that that scale goes up to 42, so 0 through 3 would be mild strokes. Um, these were patients in China. About 5000 patients were enrolled. Um, these are patients who did not get thrombolytic therapy. Um, they did also not have any ongoing indication for anticoagulation, so that goes back to the non-cardiombolic portion of the guideline recommendation. Uh, these patients were given a loading dose of Plavix, 300 mg or clopidogrel, followed by uh daily clopidogrel for 21 days, as well as aspirin for 21 days. And the end point here was looking for a combination of ischemic or hemorrhagic stroke with a safety endpoint of moderate to severe bleeding. Just to jump to the results here, uh, there was a significant reduction in, um, all strokes, so stroke being either ischemic or hemorrhagic stroke, which is the primary outcome. Um, the P value you can see there in red was circles. Um, there was also a reduction in secondary outcomes of stroke, MI, or death from cardiovascular causes, uh, significant reduction in ischemic stroke, and then as far as safety outcomes, there was no significant worsening of bleeding outcomes, um, statistically speaking. Here's a Kaplan Meyer curve looking at the reduction in events with the combination group, and overall the hazard ratio was 0.68 with the number needed to treat of 29 patients to prevent one stroke over the course of the study, and with no number needed to harm, meaning there wasn't any statistically significant increased bleeding risk in this trial, at least. So to summarize this data, uh, the combination of aspirin and Plavix for these mild strokes, non-cardiobolic strokes for 21 days was shown to have reduction in recurrent stroke or TIA, as well as, uh, not showing any significant increased risk of bleeding, with the number needed to treat of 29 to prevent one stroke, whether that's hemorrhagic or ischemic stroke and no number needed to harm. So the trial was replicated 5 years later in the United States and other parts of the world, Europe, um, Australasia, uh using aspirin and Plavix for 90 days, so a little bit longer after a mild stroke or TIA. The goal here was to start even sooner within 12 hours of the index events. These were 269 medical centers um around the world, like I mentioned again about 5000 patients. Uh, again, a high risk TIA. By clinical features or a low uh severity stroke with an NIH stroke scale less than 4. Again, the patients did not receive thrombolytic therapies and did not need ongoing anticoagulation for atrial fibrillation. Uh, they also did not qualify for any needs for carotid intervention. As part of the inclusion criteria for this trial, and the Plavix dose was a little bit higher, 600 mg compared to 300 mg, and again the primary endpoint was a combination of ischemic stroke, MI, death from cardiovascular causes, but again the safety endpoint of bleeding. Uh this trial was actually stopped early because of excessive bleeding signal in the treatment group based on an interim analysis. You can see here that uh there were fewer strokes, um, the composite primary efficacy outcome was lower in the combination group, again it was stroke, MI, or death from ischemic vascular causes, but there was significantly higher uh major hemorrhage as well as um minor hemorrhage in the combination group which led to the early termination of the study. Again some Kaplan-Myer curves and uh patients had fewer events in the uh primary efficacy outcome with the combination drug, but they had higher rates of major hemorrhage based on these um curves here. The number needed to treat with 66 to prevent one stroke. Uh, one stroke MI or vascular death, and the number beneath the harm was 200, um, or one major hemorrhage, and the hazard ratio was 0.75 for ischemic stroke or MI, and the hazard ratio for hemorrhage was 2.32. So, um, some smart people took a look at the, uh, time point analysis of points when there were events, uh, in the two groups and when there were hemorrhages in the two groups, and interestingly they found that the reduction in ischemic events, um, was really mostly reduced in that first really two weeks or so. From enrollments and the hemorrhage rate was pretty consistent throughout the enrollment period and the time that the patients were on dual antiplatelet, which suggested that potentially the time that the patient was on drug was potentially too long, uh, in keeping with the original trial, we talked about chance, which was just 21 days of dual antiplatelet. When the point and chance trials were added together in a meta-analysis, um, You can see that um overall again, there's a reduction in the rates of ischemic events when patients are on dual antiplatelet, but when you combine the two studies together, you see that there is a higher rate of major hemorrhage when you compare the two groups, uh, and that the rates of hemorrhage is persistent all the way out to the end of the 90 days, um, which is probably the contribution again from the data from point, which is when the patients were exposed to drug again quite a bit longer, 90 days versus 21 days. And again, another group of people looked at the time course and saw again that the events, the ischemic events were particularly reduced in that 1st 2 to 3 weeks, whereas the hemorrhagic events uh persisted out again to the end of that 90 day period suggested again that the risk of hemorrhage was during the time course of the dualantic platelets and the reduction in risk was in that 1st 2 to 3 weeks, suggesting that the main benefit of the dualantic platelet seems to be in that 1st 2 to 3 weeks. to summarize the um the evidence between uh the evidence of aspirin and Plavix in the short term, uh again the chance trial 21 days was positive for the benefit of dual inta platelet in the 1st 21 days after a mild stroke, mild ischemic stroke, or high risk TIA with no increased risk of hemorrhage. The point trial. Which was 90 days of dan the platelet had mixed outcome and was stopped early due to excessive bleeding. Uh, again, a secondary time course analysis suggested that the benefit was really in that 1st 21 days, and the pool data between the two trials suggested that the optimum timing is probably sometime in that 1st 14 to 21 days in order to reduce the risk of hemorrhage and uh to really target that uh higher risk of ischemic stroke um compared to the monotherapy group. And then recently, uh, it's 5 years ago now, the thallus or Tally's trial was completed, uh, specifically looking at aspirin and Teagular for 30 days, uh, after a mild stroke or TIA again with high risk features, uh, and in this case they allowed a little bit more uh serious or intense strokes with the stroke scale all the way up to 5. Again with a range of 0 to 42, it's still a relatively mild stroke but um allowed for some patients with more severe features to be enrolled. These patients were started within 24 hours of the index events. Um, these were 11,000 patients in 28 countries and the primary endpoint was a combination of stroke or death with a safety endpoint of bleeding. And again another similar uh Kaplan Meyer to the point trial, um, we have a reduction in stroke or death with a P value of 0.02. We have an increase in severe bleeding with a P value of 0.001, with an overall hazard ratio for ischemic stroke or death of 0.83. And a number needed to treat of 92 to prevent one stroke, and a number needed to harm of 263 for severe bleeding with a hazard ratio of 3.99. So overall, a significant reduction in recurrent stroke or death, but at the cost of significant increase in severe bleeding. So to put all these three trials together, we have um probably the highest level evidence from the chance trial showing in 21 days of aspirin and Plavix together reduce the risk of recurrent stroke or vascular events, um. Compared to antiplatelet monotherapy without the increased risk of hemorrhage, that is obviously the concern of giving this extra antiplatelet agents, uh, looking at the time course, you know, if a patient has another risk for bleeding, for example, you potentially could target that to 10 to 14 days based on secondary analysis. Uh, the point trial, um, replicated in other parts of the world outside China was again d on the platelet, but for a longer duration of 90 days showing a reduced recurrence of stroke, but was stopped early because of excessive bleeding risk. I would say it's a little bit hard to compare apples to oranges here and ischemic stroke compared to a hemorrhagic stroke where hemorrhagic strokes can certainly be more um severe and more life threatening, but um a secondary analysis again of this trial showed that the possible benefits um was limited to the 1st 21 days in the setting of that uh ischemic stroke being reduced during that time point compared to other points of the trial. And when you pull the data together from those two trials, you see that the particular benefit is in that 1st 2 to 3 weeks. Uh, and then in a special case, uh, with thallus, potentially if a patient has an allergy to, um, Plavix or is it Plavix non-responder, if you already know that, then there is a role potentially for aspirin and caular for 30 days, which showed a reduction in recurrent stroke, but again the tradeoff of a higher bleeding risk. So I think the takeaway here is again the highest level of evidence probably for 21 days of reduction of recurrent stroke and that's shown up again in the um EHAASA uh guideline which is again level 1A. uh again if you have a patient who has a higher bleeding risk than others and you're concerned about um exposing them to the drug, then you potentially could reduce that beyond um below the 21 days, potentially to 10 to 14 days if they are an intermediate risk. And again this is limited mostly to patients with low risk, uh sorry, high risk TIA or low intensity, low severity stroke, um, again milder features of the NIH stroke scale being less than 4 or a high ABCD2 score indicating a high risk TIA. Uh, the longer duration of the combination of the aspirin and Plavix is not well supported. We'll talk about that briefly and the, um, again, special population. Who may not be Plavix responders if that's already known to you, um, they may be potentially a candidate for teagar and aspirin, but again, the increased risk of bleeding is there. So overall I think again the highest level of evidence, a purely true trial or purely positive trial would be the chance data for that 21 days, which again is um mentioned in the uh the guidelines from 2019. So our system, BJC, I realize not all of you are in our system, but the BJC system um recently uh adapted a an order set in our EMR to deploy the use of this to hopefully increase the um the uptake of the dual antiplatelet therapy um short term course. Um, it's taken some time to get that deployed, but we finally put uh put that together in February. Again, it's these are patients with low NIH stroke scales or high risk TIAs. Uh, the goal is to start these patients early within the 1st 24 hours and to really keep them to just 21 days of therapy. And, and one of the reasons why I'm talking to you all today is because again we just implemented this in their system and you'll probably be seeing some of these patients coming out with a short course of Plavix. The goal and the order really is part of this order set is um is designed to keep that um. Exposure to the dualentic platelets to again that 21 days, we're not really wanting these patients to be refilled on the Plavix. We'll talk again about the data for long term dualentic platelet which is very limited and uh potentially harmful, and, uh, so again if these are patients who were started on the dualentic platelet because of the stroke or TIA, the goal again is to get them to discontinue within 21 to 30 days. So again, the question is why not just continued on the platelet anti antiplatelet therapy indefinitely. I think you guys probably realize, of course, with more antiplatelets, then there's more risk of hemorrhage and hemorrhagic strokes again and hemorrhage in other parts of the body could certainly be life threatening. Uh, back 20 years ago, the match trial looked at that very question looking at Plavix, um, common dosing 75 mg compared to Plavix in addition to aspirin. Uh, this was, uh, 7600 patients with a recent stroke, but we're talking about in the last 3 months, not necessarily in the last 24 hours compared to the other trials we talked about, and these are patients who had some other risk factor as well. These were mostly enrolled more than a week out from the index events and treated for a year and a half, and the primary endpoints were MI, stroke, vascular death, re-hospitalization from the ischemic events. Um, and there was no reduction in the primary endpoints, uh, so again 15.7% for having a primary events over that year and a half compared to 16.7% in the monotherapy group, non-significance, and there was a higher risk of life threatening major and minor bleeding, which is indicated here. Uh, so all of these were significant life threatening bleeding was increased in the dual antiplatelet therapy group, major bleeding was increased and minor bleeding was increased. So almost uh 3% versus about 1% in the life threatening bleeding group. And then another trial, um, I guess now 13 years ago, SPS 31 group of that uh 2 by 2 study looked at uh dual antiplatelet versus monotherapy. These are patients with lacuna strokes, which are small vessel strokes, uh, within the last 6 months. So again, recent strokes but not hyper acute or acute. Um, they were enrolled at least 2 weeks after the events with either aspirin versus aspirin and Plavix, and they were treated for 3.5 years. The median time to enrollment was about 62 days, so about 2 months after was the median enrollment, and the end point here was recurrent stroke, either ischemic or hemorrhagic. And again there was no benefits. Uh, this trial was actually stopped early because of the increased hemorrhagic rates and no significant benefit in reduction of the primary endpoints both um futility from the efficacy standpoint as well as harm from the hemorrhage standpoint. There was a higher incidence of all hemorrhage, as well as death, a higher rate of CNS hemorrhage, but not statistically significant as indicated here. So again, all hemorrhages were increased statistically, uh, death was statistically higher in the combination group and there was again more numerical um CS hemorrhages, but not quite statistically significant. So after all that, uh, basically, aspirin and Plavix has its use, um, after a stroke, but really it's limited to the short term, the near term, immediately after, ideally with getting these patients, uh, on the dual ant for 21 days and then stopping again, there's some role for potentially 30 days with the thallus trial if that patient has a particular indication for using that group compared to aspirin and Plavix, but the majority of the patients that you'll probably be seeing are gonna be on aspirin and Plavix. Again, the data is there to support 21 days, the data is not there to support long term use of dual anti platelets, and so we do recommend again that that be stopped in almost all cases, um, unless there's some very extenuating circumstance, uh, by that 21 to 30 day mark. And um these long term trials as you saw, showed that there was um increased risk of bleeding as well as um fatal um fatal life threatening bleeding um during the time course of longer use for dual antiplatelet. This is just kind of a summary slide uh on the data that we talked about so again short term is is very helpful in reducing the risk of stroke and number needed to treat on the chance trial was in the 20s, I think it was 29 and um the uh there was no number needed to harm. There was no significant increased risk of hemorrhage in that group, so we try to use that data as much as we can the 21 days, but the longer term use of dual antic platelet does have harm associated with it. So I try to think of this as kind of a booster. Um, I think it's probably a new use for a lot of people. Um, most of the time people are on Plavix, they're on it long term or at least for uh cardiac indications they may be on it for 6 to 12 months, but for us we really think of this as kind of like almost like a Medrol dose pack, uh, just a few weeks of the drug and then um not refilling it. A lot of times we'll actually send the patients home with the bottle and that way. doesn't go to a pharmacy, there's not a refill on it. Not everybody wants their medicines from the hospital, but I think that is one way of kind of mitigating some of that risk, although again when they show up for their transitional care visit, they'll have a new medicine on board and again we're trying to make sure that everyone's aware of that as being more of a booster, uh, such that they're not um on long term anti-thrombotics with d on the platelets, um, but just that short course. So I'll go ahead and see, um, that's the first kind of half of the discussion. The next half is more about the transmission of care visits and other ways of kind of reducing secondary stroke, uh, risk factors. So I think it might be a good place to stop and see if there's any questions on dual anti platelet. I apologize, I can't see hands or the chat actually I don't see anything in the chat or in the Q&A as of right now. Oh wait, hold on. Right as I say that. So do you recommend not using an Leunar stroke. Uh, lacuna strokes, uh, being a non-cardiobolic cause of stroke, you know, I would treat those the same with the short course of, uh, dual anti platelet if the patient qualifies from a clinical standpoint. Again, mostly looking at again whether they got thrombolytics, whether they had a low stroke scale, whether they had a TIA. With a stroke, of course, if you have a lacuna stroke, then it's not a TIA, but if it had a low stroke scale, they didn't receive lytics and they weren't going to need anticoagulation for some reason, then I think that that would be a certainly reasonable candidate for those patients. The SPS3 trial is the only one that really mentions um lacuna strokes, and that was again the long term course of dantic platelet, and I wouldn't advocate for long term use of dantiplatelet in almost all patients. And then let's see, um. What about patients that show up in my office after the 24 hours with history of stroke but are not on dual antiplatelet? And that's a very good question. If your patient just kind of walks in off the street and has recently had stroke symptoms, um, you know, in the last 2 or 3 days, I would still recommend having them go to the ER. So we're not talking about the acute management of stroke so much today, but there are things that are somewhat difficult to get arranged in the outpatient setting for patients with mild strokes or TIAs, um, including carotid dopplers and getting someone's. Carotid screened and potentially intervened on in a short time course really in the first week is guideline based and so if you have a patient who's again walking in off the street or calling your office with stroke-like symptoms or TIA symptoms in the last, you know, 2 to 3 days or even up to 1 week, I think it's certainly reasonable to have them come into the ER for evaluation. And then one more, what do you recommend after the 1st 3 weeks? Just aspirin 81 mg daily? That's a good question too. So there's been um Quite a few trials looking at, you know, is more aspirin better than less aspirin and really there's a pretty wide range of doses of aspirin that have been shown to be effective and, and higher doses which we're talking about like 1300 mg of aspirin, which used to be pretty common. I was told decades ago, uh, certainly had higher bleeding risk and lower doses, but there doesn't seem to be a significant benefit in using higher doses of aspirin in the long term, uh, compared to lower doses. So we tend to be on most of our patients about 81 mg. of aspirin. There are a few situations again when they've just recently had a stroke, for example, if they don't meet these criteria, they have a higher severity stroke and they're aspirin naive, we may send them out on a higher dose of aspirin like 325s to kind of improve the pharmacokinetics to kind of give them a loading dose of aspirin to get them at steady state to inhibit the platelet activity. Um, and a lot of those situations we'll have them on 325 for a month or so and then when they follow up with us in the clinic we may reduce it down to the 81 mg that you mentioned. Yeah. Plavix is also a reasonable agent that a pretrial, um, several years ago suggested that Plavix may be as effective, if not slightly more effective. The number needed to treat was about 200, so it's not significantly, um, the effect size is really not that much better as far as aspirin, but there are certainly a lot of patients out there who don't respond to Plavix and so that makes it a little bit more tricky as far as making sure that you've had CYP testing for those patients to make sure that they respond. Uh, because unfortunately if they don't respond and you're just giving them a pro a prodrug that they can't metabolize. So in general, aspirin is what we use because we don't necessarily have to go through the testing process, which can be expensive and time uh take quite a bit of time and and aspirin almost everybody responds to. Think you're safe to move on. OK. Thanks. Thank you. All right, so what else can we do to reduce the risk of secondary stroke risk? And a lot of this is on the primary care provider, uh, to review on a regular basis with patients and obviously we look for these things as well in the stroke clinic, um. Things that are kind of run of the mill vascular risk factors that a lot of patients may not even know they have until they get to the hospital, but a lot of times we'll diagnose people with these things and a lot of our patients unfortunately don't have primary care. And uh I suspect again many of you guys prevent a lot of strokes, um, so we appreciate everything that you do. Although for job security these risk factors certainly add up and add to a lot of the risk for stroke. I think last time I checked about 80% of the American Heart Association said 80% of strokes are preventable. A lot of that. is patients who don't have a lot of access to primary care for whatever reason. We certainly try to get our patients hooked up with you all, um, afterwards, um, many of them are naive to PCP. We really appreciate the work that you guys do on preventing strokes. I don't get the uh benefit or the honor of ever preventing strokes. I always deal with kind of the after effects of stroke, but we certainly screen our patients for secondary stroke reduction, uh, after they've been with us in the hospital. Again, these are ischemic strokes that we're mostly talking about, although certainly hypertension. Is a common risk factor between both ischemic and hemorrhagic stroke. Uh, hypertension, we'll talk about, uh, hyperlipidemia, impaired glucose tolerance and diabetes, um, sleep apnea, especially obstructive sleep apnea and tobacco use. I'm not gonna be specifically addressing, although I certainly can answer questions about some of the things that we talked about, um, like inpatient workup including carotid stenosis, uh, cardiac thrombo. Atrial fibrillation, um, but certainly that's a very common risk factor. Uh, most of that kind of work for looking for those things starts in the hospital with things like cardiac monitors, carotid screening, those kinds of things, um, intracranial or extracranial atherosclerosis, which again we typically screen for in the hospital and try to take care of those things, um, in the moment rather than deferring those to you all in the PCP office. And then lastly, obesity and sedentary lifestyle, which certainly um there are data to support being active and not being um sedentary, but um the data is certainly not as robust as some of the other things that we'll talk about today as far as medications or interventions. And then there's a few stars here, a few ass on things that have limited data but still have guideline bases. um, so diabetes unfortunately, the data is somewhat lacking. We'll talk about that, uh, the treatments for OSA and tobacco use certainly have their role for um overall health and wellness for patients. The data for secondary stroke prevention is a little bit lacking, but certainly it makes sense to tell our patients to treat their sleep apnea and tobacco use and diabetes for a host of other reasons, and again there are guideline bases that we'll talk about here. So this is um the second presentation that I've actually taken from so the the theme changes here a little bit. I apologize, but um we've got blue now. Hypertension is very common. You guys probably see hypertension a dozen times a day at least, um, but 70% of our stroke patients that we see, ischemic stroke patients have had, um. Hypertension or have hypertension um back from the data here from the 2000s, about 60 to 70% of patients again with a history of stroke or hypertensive and it's probably even higher now as the population gets more overweight, more obese, more metabolic syndrome. Uh, not only are our patients hypertensive, but the patients with more hypertension or higher degrees of hypertension are more likely to have a secondary stroke. So these are patients who had a second stroke and looking at the overall relative risk of having a second stroke based on their cyst. And diastolic blood pressures and as you get further to the right, it's higher blood pressure, so patients with 160 to 170 range or higher blood pressures uh had a relative risk of a second stroke that was much higher than someone who had a range down in the 120 to 130 range, which makes sense. A number of trials back in the 90s and early 2000s looked at treating blood pressure and how that affected secondary stroke risk. Here's the names of a few of those. I'm not gonna go through the innate details here, but this is a meta-analysis looking at several trials during that time period. And basically the take home here is that if you treat someone with blood pressure medication after they've had a stroke, the risk of recurrent stroke is lowered, which again makes sense. And then most recently in 2023, a meta-analysis looked at intensive versus less intensive blood pressure goals on the risk of recurrent stroke, and this looked at 10 RCTs across many years going back again to the 90s, it excluded some drug comparison trials looking at specific um types of drugs like ACE inhibitors versus calcium channel blockers, but it did allow for multi-drug versus placebo. It included over 40,000 patients again from the 90s up until 2019. And we'll see some um some charts here basically that the lower blood pressures were associated with the lower recurrence rate of stroke. So this is the names, uh, these are the names of those um trials that were included in the meta-analysis, and then the meta regression here on the right and figure 2 shows that again with more systolic and more diastolic blood pressure reduction, the risk of a recurrent stroke was reduced in somewhat of a linear fashion here. This also shows that the more systolic, this is from the same paper in meta analysis, the more systolic blood pressure reduced and the more diastolic blood pressure was reduced, the number needed to treat dropped. So if you had patients drop their systolic blood pressures by 10 or 11 points, you could potentially reduce uh a stroke if you had 14 of those patients. Um, and again, if you dropped 114 patients by 4 millimeters of Mercury and diasto blood pressure you could prevent a stroke. So again, this all goes back to secondary stroke prevention, but again it goes back to the fact that you all in your day to day jobs with blood pressure are preventing a lot of strokes. Again, it's not great job security for me, but we have enough strokes going on already, so we don't necessarily need them, and we really appreciate again the work that you do that we don't ever really appreciate, um, because those patients never hit the hospital. So again, this again suggests that um if you can get your patient's average blood pressure. Pressure is down by this much 10 points, that's uh if you treat 14 of them, you know, you're preventing a stroke in the secondary risk population. So again, a lot of um appreciation for what you all do and it really does mean again preventing these patients from complications. I think we struggle a lot of times with our patients not realizing that, you know, high blood pressure is, is something that oftentimes doesn't have symptoms until it ends up being something that causes a lot of symptoms like a debilitating stroke. So, um, I go quite fast here, but hypertension is very common. 70% of our stroke patients have a history of hypertension. Um, the observational studies that we alluded to show that again people who have higher degrees of high blood pressure have higher recurrence rates of stroke. There have been a number of RCTs over the years showing that intervening on blood pressure is an important way of reducing the recurrence of stroke and that meta-analysis that we just looked at suggested that the lower the blood pressure, the lower the recurrent rate is for stroke. The AHA and ASA has adapted um recommendations for blood pressure treatment for patients with hypertension after a stroke, which is level one evidence. There is not a specific target number that has been borne out by evidence, but again, the meta-analysis that we've looked at as well as primary prevention data supports using 130/80, which has made its way into the AHAASA guideline. This is the 2021 secondary prevention of stroke guideline for a level 1B recommendation for less than 130/80 in most patients and. And it did target um or it did lie out in that guideline that there may be some role for more liberal blood pressures in some patients who are elderly or who have more um side effects of having low blood pressures. But in general, your typical healthier patients under the age of 75, 130/80 is a very reasonable target and again is a level 1B recommendation for blood pressure, uh, target. I'm gonna go ahead and move on to hyperlipidemia. If there's a lot of questions, uh, Nikki, feel free to, to stop me here. I have about 5 of these total and I'm making pretty good time here, especially because I started a little bit early, but hyperlipidemia is also very common. Um, it's about 30% of our stroke survivors, um, I suspect even more, um, in the future again with the increased incidence of metabolic syndrome, obesity. Um, the observational studies that are out there from different parts of the world have suggested that the higher degrees of serum LDL, especially LDLC, and, um, higher incidence of recurrent stroke rates, as well as primary stroke rates, and there are a number of primary prevention trials which show that cholesterol medications, especially statins, uh reduce the risk of stroke and, uh, especially cardiovascular disease. I think one thing that we oftentimes will talk about is that, um, The overall incidence of cardiovascular disease and stroke, uh, for many, many years was was kind of plummeting in between I think the 1950s and the 2020 early parts of 2020. Unfortunately those risks of stroke are starting to creep up now after kind of um the deering down into the late 2010s and early 20s, um, some of that may be related to things like COVID and other things that were associated with thrombosis, but also we're seeing obviously the increased risk of obesity and ditabolic syndrome which is probably adding to that risk as well. But I think that we have to uh point out obviously that these medications for hyperlipidemia and statins in particular are a big part of some of the reason why people are living longer, why they're having uh reduced risks of stroke, as well as a cardiovascular disease. The major trial looking at statins for stroke prevention, um, there's two that I'll talk about here, but there are other smaller trials. Um, so sparkle was the first major randomized control trial for statin use specifically using atorvastatin 80 mg versus placebo, and these are patients who had a recent stroke in the last 1 to 6 months who did not have heart disease because at that point there was already indication for patients with heart disease to be on statins. The patients were limited to enrollment if they had an LDLC of 100 to 190 and uh they were supposed to stop their treatment with statins before enrollments. Um, we'll look eventually here, but a number of the patients ended up crossing over from placebo into the treatment group and so there was some potential interaction from um some biases from patients being put on statins regardless of whether they were in the placebo versus the treatment group by their primary care providers, um, for example. There was um enrollment for both ischemic stroke and TIA but also there was enrollment for hemorrhagic stroke, which we'll talk about here in a little bit if the patients were deemed to be at risk for ischemic stroke or had cerebrovascular risk factors um that would predispose them to cardiovascular disease as well. So those would be things like intracranial atherosclerosis, carotid artery disease. Patients were excluded if they had subarachnid hemorrhage or a known cardiobolic source for their stroke or something like atrial fibrillation. Uh, these patients were followed for a fairly long time, about 5 years. Um, the end point was all strokes, and, uh, at the end of the trial, the LDL and the control group was 129 and the treatment group it was about 55 points lower at 73. Um, at the end of the trial, 11.2% of the patients um in the treatment group had stroke and 13.1% in the placebo group, which was a P value of 0.03%. Um, the relative risk reduction was 16% with the number needed to treat a 46% over the course of that 5 years. In subgroup analysis, there was a significant reduction in fatal stroke but not non-fatal stroke. There was a significant benefit with cardiovascular events, um, mortality overall was not affected. There was a significant number, like I mentioned, the patients who were subsequently prescribed statins from their providers, and this was an open label indication from their providers. Um, 25% of the patients in the placebo group ended up being on statins by the end of the trial, whereas only 11% of the patients in the treatment group ended up starting a second statin, which I found somewhat interesting. Um, and then a significant number of the patients have, there was a significant increase in the incidence of hemorrhagic stroke in the treatment group, although in both groups it was a fairly low incidence, but it was 2.3% versus 1.4%. This is a meta-analysis looking at interventions for cholesterol on the recurrence of stroke, and the top half of the page here is looking at trials with statins and the majority of these patients. are from the, so the weights of these meta-analysis, uh, majority is from the Sparkle trial. There's also very limited data here on fibrates, fibrates overall were not found to be um reducing the risk of recurrent stroke, whereas statins were again heavily weighted by the sparkle trial. More recently, we have the uh advent or invention of the PCSK9 inhibitors. Um, the Fourrier trial was a mixed primary and secondary prevention trial from 2017, and this was a very large group of patients, 27,500 patients with cardiovascular disease. Uh, not all of whom have had a stroke. Only about 20% of the patients, 19% had had a previous ischemic stroke. Um, these are patients who were randomized to either evolleumab or placebo, and, uh, the baseline LDLs were all over 70, uh, or the non-HDL was over 100 while they were taking a statin. 81% of them were previous MI patients and so again the weight of this trial is mostly cardiovascular disease, but 19% had had a previous ischemic stroke. Some of them also had uh peripheral artery disease. Uh 70% of the patients before enrollment were on a high intensity statin, and 30% were on moderate intensity statin, and the primary outcome was cardiovascular death, MI. CVA cardiovascular accident or sorry surrovascular accident, unstable angina admissions or coronary revascularizations. Uh, again, very similar to the um sparkle trial, the intervention dropped the patient's LDL by over 50 points. Um, so here it dropped between 50 and 60 points between placebo and the intervention group. And as far as the outcomes go, so the primary endpoint was reached um with a higher ratio of 0.85, so 9.8% of patients had cardiovascular death, MI, stroke, hospitalization for angina or coronary revascularization compared to 11.3% in the placebo group. Uh, also there was a reduction in stroke risk in the intervention group with a hazard ratio of 0.79, and that included both um ischemic stroke or TIA as well. And then uh also reduce the risk of uh death numerically, but not statistically, pretty similar between the two groups, um, but numerically, um. Sorry, there was equal events. I'm sorry, as far as death from many cause my apologies. Um, the P values were significant for stroke, uh, ischemic stroke or TIA, and the primary endpoint which was again cardiovascular death and my stroke hospitalization for unstable angina or coronary revascularization, my apologies. As far as what is the target for LDL that's a very good question, and it's been defined over the years differently. Um, the short answer is it's not really been specifically tested with an RCT, but there are guidelines to help us with those. Um, the post hoc analysis of the Sparkle trial, which was again atorvastatin 80 mg, showed that the patients that did achieve LDLs of less than 70 mg per deciliter had statistically significant relative risk reduction of 28% of all strokes, which was higher than the overall group without a significant increase in hemorrhagic strokes. In 2018 to 2019, the acute management of stroke patient guideline which is available for free online, is usually used for us in the hospitals uh setting, uh, showed that for patients who are under 75 who have a um An LDL of over 70 mg per deciliter. We want to try to target at least a 50% reduction in LDL. That's a level one a recommendation. And then there's data to support that if patients have over 70 mg of deciliter on the intensity statin that they can, the highest intensity statin that they can tolerate, then we recommend considering Zetia or the PCSK9 inhibitors based on net benefit and costs. And so that last one is a level 2AA recommendation. This is a pretty busy slide here, but basically summarizes what we just talked about as far as hyperlipidemia, um, and so we see that hyperlipidemia is also very common in our patient population stroke or TIA history. The SARCle trial showed us that there was a reduced risk of stroke with the initiation of statin, high intensity statin. There was a significant increase in hemorrhagic stroke. If you look at the subgroup analysis from that data sets, um. There's a suggestion that the patients that had the risk of hemorrhage were the patients uh which was more dramatically elevated than the patients who had a history of hemorrhagic stroke that were included in that trial, and that's led to quite a bit of discussion about You know, what do we do with patients with hemorrhagic stroke history, especially if they have an ischemic stroke history in the past. Um, there's some ongoing trials right now looking at removing statins for patients who have a history of both ischemic and hemorrhagic stroke. Um, we certainly don't start our patients with hemorrhagic stroke on statins, um, in the acute setting, but we do oftentimes. I know that those patients have risks that are outside of the hemorrhagic stroke as far as the ASCVD risk and so some more data to come on again whether those patients with a history of hemorrhagic stroke may um benefit from stopping statins. That's something again that will need to be borne out with some trials that are ongoing at this 0.1 of which is called Saturn that we're participating with at Washington University. Uh, meta-analysis again heavily weighted by sparkles, suggested that there was a benefit reducing all strokes, but there was an increase in hemorrhagic stroke. It was a small group overall, but 2.3% versus 1.4%, um, again suggesting um higher dramatic effect in the patients with a history of hemorrhagic stroke, like I mentioned, in patients with cardiovascular disease with a residually elevated non-HDL cholesterol, the addition of PCSK9 inhibitors significantly reduces the risk of stroke. Uh, the ischemic stroke patients with no cardiac source of embolism. So again, that was the exclusion from the Sparkle trial and excluded patients who needed to be on anticoagulation, if we knew that they had atrial fibrillation, etc. and who had an LDL of greater than 100 mg per deciliter should be started on a high intensity statin. The guidelines suggest atorvastatin 80 mg, but there are other high intensity statins, and it makes sense to potentially use those, especially if your patients have non-tolerance of their statin medications. Uh, for stroke prevention, that's a level 1 A AHA and ASA guideline. Ischemic stroke patients with atherosclerotic disease, which is also a fairly big chunk of our patients with stroke, should be on a statin with a goal of less than 70 mg per deciliter to reduce the risk of subsequent stroke. If they can't get there with just a statin, then we recommend uh considering Zetia or the AHA ASA also. recommends that and then patients who are at very high risk based on ASCVD calculator, um, which is stroke plus any other risk factor, who are already on a maximally tolerated statin um and Zetia with an LDL of greater than 70 mg per deciliter, it's reasonable to consider PCSK9 inhibitors. That is um a bit nebulous when it says to consider the guideline itself recommends taking into consideration cost benefit analysis. Um, it also mentioned at that point that the burden was um quite a bit higher than other interventions available, especially with the cost, um, but I do know that more recently the costs have come down for some of my patients and it's been easier I know for some of them to be put onto some of these medications as those medications become more affordable. I think I'll stop there. Those are the two big ones as far as hyperlipidemia, hypertension. Any questions about hypertension, hyperlipidemia before I move on to some of the data that's a little bit less uh straightforward on diabetes, OSA, smoking. Yeah, there was a question in the Q&A. Um, patient presented to our office with what sounds like a TIA within the past 1 to 2 days with resolved neurologic symptoms. How do you suggest that we work this up? Yeah, that's a good question. Um, going back to kind of what I said earlier, um, there is quite a bit of burden in getting a TIA workup done in the outpatient setting, and so I do recommend for most patients that have had a TIA or mild stroke in the last few days to go to the emergency room. I know that our emergency rooms are oftentimes overwhelmed, but there's just a lot of things, especially with risks associated with carotid disease that need to be taken care of sooner rather than later, um. And so I would say that the fastest way to get that done is through um a visit to the ER. We do have, this is not to advertise at all, but there is a TIA unit at Barnes and the goal there is to kind of get things done within 24 hours. I would say for counseling purposes, most of my patients can get in and out of the hospital within 24 hours. In fact, their insurance kind of mandates that they're in and out within 20. 4 hours for TIA, it's not reimbursed beyond that, but the key things there would be looking for carotid disease, making sure they don't need a revascularization, um, looking for telemetry, and also monitoring them to make sure that they don't have recurrent stroke because the ABCD2 score, if you look at it online, if you just Google it briefly, you can kind of get a sense of what the risk of having another event in the next 2472, um. 7 days are and uh especially if the patient had weakness or speech issues that risk is um is much higher and so, you know, making sure that they're observed if they were to have a recurrence that they're in a place where they could get thrombolytics or assessment for uh advanced interventions, that's what I typically recommend my patients. Mm. I think you can move on now. I think that was, that was the only question. OK. Another part of kind of answering that question too is that we oftentimes kind of, you know, hold off on people's blood pressures if they're having a TIA or stroke because we want extra blood flow to go to the brain and so if that patient that you mentioned is, you know, on blood pressure medicines, we don't necessarily want to artificially lower their blood pressures with their medicines and again doing that in a monitored setting is in my opinion, safer than doing that in the outpatient setting. The, um, the next few slides here are on diabetes and impaired glucose tolerance. Um, again, this is a fairly common, um, risk factor, about 11% of US adults in general have diabetes. It's higher incidence in older patients who are over 65, 27%, um. Over 12% in non-Hispanic blacks and um it's, there have been some observational studies showing that between 60 to 70% of patients with a history of stroke or TIA have impaired glucose tolerance and 25 to 45% meet criteria for diabetes. And um The, uh, patients that do have diabetes, unfortunately have a higher risk of recurrent stroke as well, with some observational studies attributing um higher, 60% higher risk of recurrence compared to non-diabetics. So this is a, a study from 20 years ago, but this was a Look at, you know, what types of risk factors were observationally associated with having recurrence, diabetes is one of the highest here, about 60% more likely to have a stroke compared to non-diabetics. Smoking was the highest at uh over 200% compared to non-smokers, and um there's some other things on here like Afib and hypertension, but, um, diabetes is certainly on the higher end of things here. Unfortunately, there haven't been any large randomized control trials looking at the long term effects of intensive versus standard control of diabetes after stroke, so secondary prevention trials um don't exist, looking at the specific, uh. Um, goal of, you know, does more tight control of blood sugars affect the risk of recurrent stroke. There were some trials that were done in the short term, so the biggest one being the Shine trial from about 5 years ago, looking at randomized intensive blood glucose control through a drip, an insulin drip within 12 to 72 hours after a stroke, and there was no significant improvement in 90 day outcomes for those patients and there was more hypoglycemia, um. It was a bit of a challenging trial, um, you know, patients needing to be on an insulin drip in the setting of an acute stroke, but, um, unfortunately no significant improvements there and certainly more hypoglycemia. There's also been a quite a few trials looking prospectively and retrospectively for patients with intensive versus more liberal control of diabetes in the primary prevention setting. And um pool analysis of those patients did not show a significant benefit in tight glycemic control on stroke, uh recurrence or stroke, uh primary stroke, but the um AHA and ASA would comment on the next bullet point that there's significant benefit with regards to microvascular complications with intensive blood sugar control. So obviously, we don't want our patients to become blind or have significant retinopathy or significant neuropathy or nephropathy. I know you just had a talk on neuropathic pain, um, you know, a lot of patients can avoid those. Microvascular complications if they have tighter control of their diabetes. Um, so, whereas there's not necessarily a direct correlation or causation between tighter blood sugar control on recurrence of stroke, the AHA and SASA still have a level 1A guideline for more intensive blood glucose control with an A1C of less than 7%. Again, that's more to deal with the microvascular complications, some of which are neurologic with retinopathy and neuropathy, but um unfortunately, the data is either limited or non-existent on the benefit of stroke recurrence. Um, it does remain However, uh, the, uh, level 1 A recommendation for less than 7% for those microvascular complications. I'll summarize this at the end here, but again, the, the take home from that would be level 2B usefulness of intensive glucose control beyond the acute phase unknown for prevention of recurrent stroke. As far as um more recent, uh, medications, obviously GOP ones are very hot topic in a lot of scenarios, um, from stroke to OSA to all kinds of different things that I'm seeing, um, pretty much on a monthly basis in medical journals, but in 2019, a fairly large trial called Rewinds looked at um GOP1 receptor agonist uh Trulicity, um, over the course of 5.5 years to um. Seeing if it prevented MI, CVA, and death. This is mostly a primary prevention study, but it's a fairly large trial, so 9900 patients, 31% of them had cardiovascular disease. Um, there was a significant reduction in the primary composite, so hazard ratio of 0.88. Um, the secondary endpoint of all stroke was also significantly reduced with the hazard ratio of 0.76, uh, with a significant p value of 0.01. There was a pre-planned subgroup analysis for the primary composite endpoint based on patients with a history of cardiovascular disease. There was no um significance there for patients who had a history of cardiovascular disease, but this was probably underpowered in the setting with only 31% of the patients with a history of cardiovascular disease and even fewer of those with a history of stroke. Uh, there were no significant adverse effect differences and as far as again primary prevention, this. has led to a lot of our patients being able to qualify for some of these medications even though some of them are fairly costly because there is evidence for primary prevention from stroke and heart attack. Um, as far as the secondary prevention data that still needs to be borne out and uh even last month there were some papers being presented at the International Stroke conference on the role for these medications for stroke prevention, and I think that the next phase is probably secondary prevention for a lot of our patients. Uh, these are so new at this point still that they're not reflected in the AHASA guidelines, although we're probably due for some new guidelines for acute stroke management in the next year or two, so that's to be borne out in the next few years. Uh, the data here again as I mentioned at the very beginning of this half of the top, uh, topic is fairly limited. The diabetes and insulin resistance are certainly associated with an increased risk of stroke. The primary prevention data does not show the reduced reduction, the reduction in stroke risk with intensive blood glucose control, but the microvascular complications are certainly reduced with more intensive control. And so it's still the level 1A guideline from AHAASA for preventing um microvascular complications with intensive glucose control. Their recommendation is an A1C of less than 7% in most patients. I know that the um uh. Other organizations have a little bit more liberal um guidance for patients with particular groups, um, especially if they're more frail or more um difficult to control with hypoglycemic events, but again for the prevention of microvascular complications, the AHA and American Stroke Association recommend less than 7%, which is what we typically use in our counseling with our patients. The um The data for primary prevention with the GOP one agonists is there. It's mixed with the secondary group, um, in that there's probably not enough power in that group that we looked at, um, but I think that more data is certainly needed for patients with cardiovascular disease history to bore out, to bear out whether, um, those could be helpful for secondary prevention, and I certainly think that there's a signal there, it's uh getting insurance of course to to pay for those kinds of studies or. Pay for those interventions with our patients with a history that can be difficult, especially in our older patient population who are on um government supported insurance that may not want to cover those in non-diabetic patients, I think in particular. Couple other Things to talk about, so OSA obstructive sleep apnea, so again very common in our patient population, so 50 to 75% of patients with stroke or TIA are found to have OSA, uh, in a meta-analysis, um, most of the patients had an AHI of uh greater than 5, so 72% of stroke patients had an AHI and apnea hypone index of greater than 5, many of them had um an AHI greater than 20, so about 40% of them had a pretty severe, uh, form of OSA, um. These are some unique factors associated with stroke stroke patients. They may have lower BMIs, they may not be as obese, um, and they may not feel as sleepy, so they may have a components um of kind of mixed apnea between central and obstructive sleep apnea in the setting of having the stroke, which can sometimes manifest again with um lower degrees of sleepiness, but can still be dangerous as far as things like blood pressure, quality of life, mood, those kinds of things. There's pretty robust data for the primary outcomes with use of CPAP in OSA, so this is a meta-analysis from 2016. And in patients who had OSA if they used CPAP, they had a reduction in the risk of stroke, as well as cardiac events and all cardiovascular events. So it makes sense, of course, to look at whether the secondary reduction is there. The largest trial that I have found uh recently, there's one ongoing right now and we're doing that at at Washington University as well called um Sleep Smart, but the SA trial was over 2000 patients, um, in multiple countries looking at um whether CPAP in patients with a history of stroke or TIA could reduce the risk of um a composite of death from cardiovascular disease, MI. Stroke and heart attack, uh, stroke and TIA, uh, CHF admissions and acute coronary syndromes. The secondary endpoint was other vascular issues like revascularizations, uh, new Afib, new diabetes diagnosis, all causes of death, symptoms of OSA including quality of life and mood, and then they looked at safety endpoints of accidents and near misses from sleepiness, um. Days off from work and um these were patients who were um between 45 and 75, they had ischemic um stroke history or coronary artery disease. They had moderate to severe OSA and they were set on a CPAP machine in automatic mode. The um primary composite points was not different between the two groups as far as CPAP and standard um therapy, basically non- CPAP group put on a wait list basically for possible CPAP. Um, the end points for stroke in particular, secondary endpoint for stroke and for hospitalization for TIA were also non-significant between the two groups. The positive cerebral events was non-significant between the two groups. There were some um other things that were different between the groups, so I thought blood pressure was better controlled than the patient who was on CPAP. The sleepiness scale, Epworth sleepiness scale was lower in the group who was on CPAP, anxiety was lower, depression was lower, um, and then a composite of um physical well-being and mental well-being were all better in the group who was on CPAP. But overall, there was no significance in the primary and secondary cardiovascular endpoints. Um, there was again like I mentioned, improvements in sleepiness, mood, quality of life, um, fewer days off from work, I thought blood pressure, and there wasn't any significant difference as far as adverse events. Um, the, uh, the study authors did notes that the adherence was not ideal, so there was only about 33.3 hours of use on the median patients, um. By the end of the study with a residual AHI apnea hypopne index of 3.7, um, the post publication secondary analysis looked at patients who have good adherence versus those who had less good adherence, and it suggested that the patients who actually wore the masks for longer periods of time, um, closer to a full night of sleep had may have had lower incidence of cardiovascular events. Of course, that wasn't um. An analysis that was planned at the beginning, that was a secondary analysis and so big caveat there, but it's being borne out now in the Sleep Smart trial which we're taking part of at Washington University looking at whether um treatment with CPAP can be associated with reduction in the risk of stroke, TIA, those kinds of things. I think I covered um the first two here um already but again unfortunately not the signals that we were hoping for as far as whether CPAP reduced the risk of secondary stroke, but certainly there's benefit with quality of life, mood, diastolic blood pressure. Um, the largest study again saved did not show any significant improvement in primary vascular endpoints, but did show those improvements in the quality of life type endpoints. And there's a possibility that maybe better adherence um may have improved secondary prevention of cardiovascular events, but that needs to be borne out with data, not just conjecture. And again, although there's no data to support secondary stroke prevention, the AHA ASA has a level 2A recommendation to use CPAP in our patients with OSA in order to improve mood, blood pressure, sleepiness, and quality of life is specifically what that recommendation says. Lastly, in the few minutes that I have left, uh, smoking. So, um, obviously, we looked at that data from earlier, um, over 200% uh rates of stroke recurrence compared to non-smokers, so twice as likely to have a recurrent stroke if you're a cigarette smoker, and, uh, at least. The, uh, in this trial or in this. Retrospective observational study, this was the highest incidence of recurrent stroke was in the smoking group. There's not been any large randomized control trials looking at tobacco cessation and stroke recurrence. Um, a lot of people would argue that's unethical to, um, to tell your patient to not stop smoking, um, given the preponderance of data associated with tobacco abuse with multiple medical issues, um, the level one a recommendation from AHA, ASA or guideline is to counsel our patients with or without drug therapy to assist in quitting smoking in order to prevent. Uh, all kinds of morbidity, but, um, stroke and TIA being part of that. And if patients do continue to smoke for whatever reason, if they're not able to stop smoking, then the recommendation level 1 B recommendation is that we should advise the patients to reduce their tobacco intake. So a couple of busy slides here basically just summarizing what we've talked about already, but hypertension management is a level 1A recommendation. So putting our patients who have hypertension on medication is level 1A recommendation. It's reasonable to target 130/80 with a level 1B recommendation. Most patients less than 130/80, um, unless they have other frailty issues of hypo um tension related issues, um, they're older, they're more likely. Fall, those might be reasons to target a little bit higher, but for most patients under 75, 130/80 is a good target for patients. As far as hyperlipidemia management, statins, high intensity statin is guideline, the highest tolerated dose of statin specifically, um, plus or minus Zia if they have a residual LDL over 70 and have atherosclerotic disease, it's recommended to start um Zetia plus or minus a PCSK9 inhibitor after discussion of their overall costs and benefits. Level one a recommendation for high intensity statin. Um, there is that increased risk of hemorrhage, uh hemorrhagic stroke in the patients who are on high intensity statin, but again, the signals that we do see are in that the, the patients who have a history of hemorrhagic stroke have the highest preponderance of statin related hemorrhage, and so we don't usually start our patients with primary hemorrhagic stroke on statins and there's still data to be borne out on whether we should stop patients with a history of hemorrhagic stroke from taking statins. Again, that's the. trial and probably gonna take a few more years to get the data from that, but that'll be interesting to see. Uh, ischemic stroke patients with no cardiac source of embolism and LDL of greater than 100 should be placed on a high intensity statin. The archetype there is atorvastatin 80 mg for stroke prevention with level 1A recommendation for patients who have already been on a statin and they have a history of atherosclerotic disease, they should have a goal of less than 70. If they're not there, as I mentioned, you know, starting them on Zetia, if they can't get there with the statin and Zetia, then considering that PCSK9, which is a level 2AA recommendation, um, the uh diabetes management is somewhat controversial in that there isn't a lot of signals because of lack of data as well as lack of um. Um, lack of primary prevention data as well, suggesting that tighter blood sugar control doesn't necessarily reduce recurrent stroke, but there is certainly a reduction in the risk of microvascular complications such that there's a level 1 recommendation for intensive control of blood sugars with a target A1C of less than 7% from the AHA and ASA. Sleep apnea management, it doesn't necessarily reduce the risk of hospitalization or stroke, but it does improve things like mood, blood pressure, and restful sleep. And so there is a level 2A recommendation from AHA ASA for use of CPAP in patients with OSA and stroke or TIA history. Uh, smoking reduction is, um, It's not been looked at with RCTs but certainly make sense mechanistically from preventing our patients from having a whole host of different morbidities, and so it's a level one a recommendation from AHASA not necessarily because of data borne out to secondary stroke prevention, but for rediction of overall morbidity in our patients. And this is just kind of a slide that says all those things in one that's a little bit less busy for you all if you wanted to take a screenshot or something like that. These are things that are oftentimes make it their way into our notes from the stroke clinic or goals on things like A1C, LDL, a discussion of something like a PS PCSK9 if the patient already has that LDL that's over 70 while they're already on the um statin and Zia, for example. So with that, um, Those are the objectives we talked about. I'll come back to this one just because again that may be the one that may be the take home from this half of the discussion, and I'm happy to answer questions about this half or the first half or both. I know I've got about 3 minutes left. I talk a lot, I'm sorry. That's OK. Um, just a lot of information. So there, here's one of the questions in Q&A. I noticed that in the PSK-9 study, the all-cause mortality was actually higher in the treatment group than in the placebo group. Studies will often talk about relative risk reduction of the primary endpoints, but absolute risk reduction is much less impressive. I would think that the death Oh wait, I would think that death is a very important outcome. Yeah, I, I would say that um for that specific question, the overall death from any cause was about equal, so 3.2 versus 3.1. Um, so maybe just a few more patients who died, you know, I don't know if they were a little bit older. I don't have the specific demographics for the patients who were included in that trial, but, uh, I would agree certainly that death is an important outcome for, for any trial, uh, whether that's a death attributed to cardiovascular events or natural death, I think that's what they try to parse out with the primary endpoint here. I'm not seeing any other questions at this time, but if anyone has any questions, um, you know, feel free to email me or if Doctor Holder doesn't mind, I can put his email address on the follow up email after the program. Yes, OK. So, yeah. All right, well, great. Well, thank you so much. I really appreciate your time and um your presentation. It was great. Thank you all very much. I appreciate it.
