professor alastair webb who is a stroke neurologic neurologist working in oxford in the uk and he will present the guideline on pharmacological interventions for long-term secondary prevention after ischemic stroke or transient ischemic attack great thank you very much so yep so quick disclosures large group of people did this guidelines there's lots of disclosures they're the ones i'll pick out for myself but nothing directly relevant specifically to what we're going to talk about today this is a group of people who've done the work um who worked very hard at the last year to put all this together it's quite a big topic as you can guess i particularly like to highlight jesse dawson who kind of led from the front and did a lot of the heavy lifting on this but it's presenting in a parallel session at the moment so i'm the co-chair the group which is why i'm here instead so second prevention is a massive topic so we're going to go fairly quickly through quite a few picots which are hard to leave any out but we focus specifically on the recommendations in four key areas applicable to all patients with ischemic stroke or taa largely speaking but not including specific etiological causes such as atrial fibrillation carotid stenosis and so on so it's the generic recommendations for secondary prevention of cardiovascular disease in patients who've had a tiaa or ischemic stroke so i'll go straight into it and focus on the blood pressure topic first of all and so fairly straightforward our first pico question was essentially in patients with a history of ischemic stroke or tia does blood pressure lowering treatment compared to no blood pressure lowering treatment reduce the risk of any recurrent stroke in particular and you may not be surprised to hear that we do indeed recommend lowering blood pressure after an ischemic severe vascular event the quality of evidence is high and the strength is that it's strong for intervention and the reason for this is because of all the interventions we have in second prevention of stroke there's quite a large number of clinical trials of blood pressure lowering versus no blood pressure lowering demonstrating in second prevention there is a significant reduction in the risk of recurrent stroke major adverse cardiovascular events or cardiovascular death in our metro analysis and systematic review there's a little bit of heterogeneity between the studies but it's predominantly dependent on profess which is the largest trial but achieved a very small blood pressure difference and there is a role for the difference in blood pressure you achieve between treatment arms and efficacy in preventing stroke so a nice solid solid recommendation to lower blood pressure is a good thing and you'll see in the pattern of the recommendations our next question we're going to talk about is how intensively should you do so should you target below 130 over 80 for clinic reading versus a less intensive target to reduce the risk of recurrent stroke in this patient population and again there's an evidence-based recommendation based on trials available with moderate quality evidence and the strength of recommendation is weak for intervention for reasons that we'll come to so essentially there's only three trials in secondary prevention randomizing to a more intensive treatment target to a less intensive treatment target with the largest being sps3 and across these trials there is a significant benefit within a more intensive treatment arm compared to the lessened intensive treatment target but it's only significant for any stroke and particularly for intracerebral hemorrhage doesn't quite reach significance for ischemic stroke or major adverse cardiovascular events and the other important point to note is that in the trials we have they're quite heterogeneous in terms of that they're in specific patient populations most the data is in sps3 which is in a lacunar stroke population in particular respect included patients with hemorrhagic stroke as well as ischemic stroke so it is difficult to say with absolute certainty that in all stroke patients that it is the best thing to lower blood pressure intensively and there are patients in whom you may not wish to do so for example patients with bilateral tight cortisone is above 70 there's evidence from the interventional cross-endotherectomy trials and that that is probably not a good thing to do and to take a more relaxed target and looking at the primary prevention literature things like the sprint trial in patients who are particularly frail elderly or have pre-existing renal disease you may also not want to be too intensive so this applies to the majority of patients there is evidence for it but you do need to pay attention to specific populations where the evidence doesn't exist and then the third question effectively is linked to two different picots how should we achieve good blood pressure control to an intensive target and for this there isn't as such good data in secondary prevention so we have two expert consensus statements instead firstly on whether to use out of office blood pressure monitoring and secondly what intervention you should use and as you can see we took the question should you initiate treatment with two blood pressure lowering medications compared to monotherapy to reduce the risk of the current stroke rather than asking about a specific class and the reason for that essentially is because as you'll see throughout this guideline there was an issue in secondary prevention whereby if we don't have evidence but that we should do something if there is good evidence in primary prevention and no evidence in the second prevention literature to disagree with the primary prevention literature we have resorted back to agreeing essentially with the primary prevention data for what you should do so for example for out of office blood pressure monitoring there are three small studies in secondary prevention of stroke and the tia which demonstrates a non-significant imply better control of blood pressure views of with use of out of office monitoring with some heterogeneity but it doesn't reach significant so in the secondary prevention data we cannot conclude definitively that out of office blood pressure monitoring is the right thing to do but if you go back to the primary prevention literature and particularly the crime prevention guidelines in europe and america and elsewhere then it was a strong recommendation that we should be using out of office blood pressure monitoring to guide effective treatment and to make diagnosis of hypertension so we have supported that with that with our consensus statement and not disagreed with what we say for everybody with hypertension just because they also happen to have had a stroke and similarly when it comes to what drugs you should use the current european guidelines have moved to suggesting that you should in the majority of patients initiate treatment with a combination of low-dose anti-hypertensives rather than a single class of agents due to equivalent or better efficacy with a better side effect profile and although we don't have direct comparison in the secondary prevention literature the progress trial in particular the arm which worked best was the group given pre-rendered plus in dapamide so there was support of data and second prevention so our recommendation is therefore to initiate treatment with a combination of antihypertensives rather than monotherapy in most patients and along with the prime prevention and support of data and second prevention we would suggest this should be a calcium channel blocker or thiazide-like diuretic in combination with the renin-angiotensin system inhibitor the again there is a small proviso that in patients who are at risk of hypotensive complications you may want to be more gentle to the elderly the frail those with orthostatic hypertension or severe flow limiting large artery disease so moving on from blood pressure to our next big topic which is lipid lowering saying the same pattern of questions so is it worth using a statin to for lipid lowering therapy versus nose statin to reduce the risk of recurrent stroke again you won't be surprised to hear that we do indeed recommend that with a high quality of evidence with strong evidence for the intervention and again this is because there are five studies which have reported specifically in stroke or and tiaa populations of schema stroke populations the benefit of using a statin particularly the sparkle study and for all recurrent stroke for ischemic stroke and for major adverse cardiovascular events there is a significant benefit from giving a statin compared to not giving a satin in all patients in the three trials on the right you do see there is a reliable evidence of a slight increase in the risk of hemorrhagic stroke intracerebral hemorrhage but this is significantly less in absolute absolute terms than the benefits you gain from reduction in ischemic events both for stroke and for major adverse cardiovascular events and there isn't sufficient evidence to say if there's any specific subgroup in whom you should not do so if they present with an ischemic event so if all patients with ischemic stroke or tia we do recommend a statin again is it worth treating to a more intensive cholesterol treatment target compared to the less intensive target to reduce the risk of the current stroke and we have made a fairly strong recommendation here on evidence-based recommendation that we do recommend treating to a target ldlc of less than 1.8 millimoles per liter to reduce the risk of major adverse cardiovascular events in particular but the quality of evidence for this is only moderate despite that the strength of the recommendation because the amount of benefits is strong and in secondary prevention this largely hinges on one trial the treating stroke to target study which used the less than 1.8 target and was in a population with atherosclerotic cerebrovascular disease and did demonstrate a significant reduction in major adverse cardiovascular events by achieving a less than 1.8 millimole per liter target this is supported by post-hoc analyses of the other big secondary prevention studies in terms of greater benefit from achieved control down to that level and it's also strongly supported once again by looking back to the primary prevention data particularly in patients with atherosclerotic disease that in primary prevention more intensive control has better long-term outcomes in prevention of cardiovascular events so we do support a more intensive treatment target how should we achieve that and similar to how the blood pressures are structured so if you've given people the statin should you add isetta mime or a pcsk9 inhibitor and here the evidence is less good specifically in the secondary prevention population we have made an expert consensus statement that we do think you should to achieve the intensive target addition of the zetta mibe is a reasonable option in the in the subtext pcsk9 inhibitors can be considered the evidence isn't quite there yet and essentially there's no dedicated secondary prevention trials in the literature and there are actually only three trials who report um the benefits in a vascular subgroup small subgroups of these very large trials in particular improve it was a population with acute coronary presentations and in the who had addition of esetami and in the cerebrovascular subgroup there was a significant benefit from adding a zetamibe and in tst they largely used asetomibe to achieve the target of less than 1.8 which is what leads us to support addition of azetamib as the the best evidenced option in patients with stroke and tia the evidence of the two pcsk9 inhibitor trials is not significant and not yet proven as an open area of research but in the right patients who would be eligible for those trials they can be they should be considered even if they have had a stroke or not so that's lipids moving on to the next very large topic is anti-thrombotic therapy and the simple question to start with in people with ischemic stroke or taa he does long-term anti-platelet therapy compared to no anti-platelet reduce the risk of recurrent stroke again you won't be surprised to hear that we have recommended an anti-platelet in ischemic cerebrovascular events the evidence is moderate to due to some heterogeneity but it is strong for the degree of benefit there's quite a lot of trials they're largely old trials they're mostly with aspirin for a single antiplatelet versus placebo there's one celosus or one declopidine trial in the in these studies but across these studies there is good evidence that treatment with antiplatelets reduces the risk of recurrent stroke major adverse cardiovascular events myocardial infarction and ischemic stroke alone there is an increased risk of major bleeding in all all tissue beds this is not significant for intracerebral hemorrhage in our in our meta-analysis but the absolute risk reduction is well in favor of treatment compared to the risk of bleeding problems most studies are with aspirin and so the best evidence is for aspirin as monotherapy but the latest studies of different antiplatelet regimens against each other do support that clapita girl is efficacious and is a is the valid preferred option in most places so moving on to should we do more than just give a single antiplatelet should we give dual antiplatelet for longer than 90 days with aspirin plus clopidogrel and we recommend against use of dual antiplatelet therapy with aspirin and clopido in the long term of note we haven't talked about the acute dual antiplatelet therapy in this guideline last year we released the expedited expedited recommendation for that so that's covered in a different guideline so although the evidence here is very low it is weak against intervention due to the potential risk of harm because there is a non-significant reduction in the five trials quite strongly driven by esps2 as well which is dipyridamol and aspirin which may not be equivalent to the aspirin classical pedigree pedigree treatment regimen for reducing the risk of recurrent stroke but there is significant evidence of an increased risk of hemorrhagic complications in particular ich so we have good evidence of harm which is significant and proven but the evidence of benefit is definitely uncertain and although those nnts suggest that there might be benefit as i say if you remove the diploma arm it's less convincing as well anyway so instead of dual anti-platelets should we use a noak in addition or instead of an anti-platelet in specific groups and there's two questions here which i've just lumped together for time purposes so the first question is should you use a low-dose noack survivor roxaband 2.5 in addition to an anti-platelet and this derives predominantly from the compass trial which was in primary prevention but did have some stroke patients in it and it did include coronary disease or peripheral arterial disease as an inclusion criteria but peripheral arterial disease included significant carotid stenosis as its definition so it is quite a few cerebrovascular type patients and it did demonstrate benefit however we don't have evidence particularly in the patients who have suffered a stroke previously which is obviously of issue in terms of hemorrhagic complications in our patients so what we have concluded is where patients were eligible to be admitted included in compass it is very reasonable whether they've had a stroke or not to consider low-dose noac plus anti-platelet for the systemic prevention of major adverse cardiovascular events they shouldn't be excluded from that treatment regimen because they've had a stroke because having a stroke was allowed to be in that trial and then the final question which i'm sure has been well worked over nowadays is no particularly after this meeting so nowhack versus anti-platelets in embolic stroke of undetermined source so when we wrote this navigate and respect trials were out atticus was presented here and all three trials have not shown any significant benefit of using a novel or anticoagulant instead of an anti-platelet in esos so we do not recommend that so quick run through this i know the final topic is diabetes and there's two picos here to finish again the straightforward question first of all in patients with diabetes who have had an ischemic stroke with tiaa does intensive control of like of glucose levels hbmc in particular compared to less intensive control reduce the risk of recurrent stroke and the bottom line is there is no secondary prevention data that we could find of any use to inform about that but in line with what i've said on the other topics if your patient has diabetes and happens to have had a stroke that does not preclude you from following the primary prevention guidelines for their diabetes and so based upon that evidence there is benefit for microvascular complications and some evidence of benefit for macrovascular complications although less certain we do recommend supporting the intent the more intensive hba1c targets of less than 53 or less than seven percent depending on which metric you use there is some question about whether how aggressive and how quick you should do that depending on how long patients have had their diabetes and what hbo and c level they start at because if you start very aggressively trying to get there quickly and some percent hba within c of 13 for five years you're going to make com hypoglycemic complications so there's a management issue there but to us colleagues so the final question which is stroke specific in terms of diabetes is whether in people with ischemic stroke or tia does use of pioglitazone compared to no pioglitazone reduce the risk of a current stroke because there is sufficient evidence for this that we felt able to make an evidence-based recommendation that despite its current under use we do recommend in patients who have insulin resistance or type 2 diabetes pyoglycine should be used to reduce the risk of recurrent stroke the quality is moderate but under strength is weak for intervention because of the potential risk of harm which we'll come to so there are three trials in this area particularly irish trial but also supported by proactive and j spirit which do demonstrate quite a significant benefit from use of pyoglitazone in this population with a 30 risk of recurrent events um there so there is good evidence for benefit and this is not there's no significant heterogeneity between the studies the main downsides the main reasons why it hasn't had good uptake perhaps is the perceived risk of harm because there was an undoubted increased risk of low energy fracture particularly reporting the iris trial so a total risk of 13.6 versus 8.8 percent of any fracture there was actually only a 1.6 increased risk of serious fracture which means that overall although there is an increased risk of complications you with the use of proglitozone the number needed to treat for benefits in terms of stroke and mi reduction is about 36 whereas the number needed to harm for fracture which is the most likely cause of disability in this population is 62. so overall the absolute benefit is in favor of glyphosate which led us to support use recommending is for treatment the other two groups in whom particular caution should be taken is patients with heart failure or at high risk of heart failure but if you have had an echo and they haven't got any symptomatic history of diastolic heart failure then that shouldn't preclude them from treatments and there is a reported increased risk of bladder cancer although with an absolute risk which probably doesn't undermine the recommendation but anyone who has had bladder cancer or particular risk factors say they report hematuria i would not go ahead and give them pyoglitazone so quite a quick run through of a big topic there are a lot of areas for future research of course in each of these areas so in blood pressure we don't have a good idea of the optimal drug class or combination for you to use in secondary prevention and in particular it would be good to prove that home blood pressure monitoring or ambulatory monitoring is useful our patients are a specific group and many of them will not be able to do home blood pressure monitoring well enough to make it worth doing so it's not proven that it is beneficial but the evidence supports it from crime and prevention and we don't know if there are specific subgroups particularly for intensive treatment where they should not be avoided they should be avoided for example intracellular atherosclerosis which you may hear about in a minute lipid lowering which drugs are beneficial after stroke pcsk9 inhibitors but there are other drugs of course coming on i don't mention them there as well but inclusion and the like um and which antithrombotic strategies are preferable as i'm sure you're aware there are new anti-thrombotics coming on the market all the time and we will hear about factory 11a and 12 factor 12 inhibitors in the next few years i'm sure which may well change what we do and diabetes it's a very old question of whether intent of hba when sea control improves macrovascular complications and i'm not convinced we're going to have any trials to answer that in second potential stroke in particular but it would be good to know but we do have questions open on which drugs are best and preferable to use so overall second prevention is good do do it there's a large burn of residual disease out there and we do recommend intensive treatment particularly blood pressure and ldlc to provide benefit with whatever means are likely to achieve intensive control at the moment a single anti-platelet strategy in the long term is the best supported anti-thrombotic strategy thank you thank you thanks a lot for this excellent presentation and for the leading this guideline i can see that there's one question really yeah thank you very much general from munich m would you recommend dual therapy in uh minor stroke or high risk tears for 10 to 21 days like based on chance and the point yes i i didn't cover it in this guideline because we did an expedited recommendation last year so it wasn't covered in the skyline but yes no for at least 21 days in that kind of we recommended dual enterprise therapy with aspirin plus clopidogrel with consideration of aspirin um [Laughter] from one point um in the particularly in the nha and ihs four to five group um so yes we do in the early phase this this guideline we specifically talked about after 90 days and the 21 to 90 days you can take your pick really depending on your interpretation of chance data thanks thank you one other question thank you very much florentine from greece i would like to address two questions uh in patients with isolated systolic hypertension would you be a little bit less aggressive so that the diastolic hypertension does not fall substantially that's a good it's a good question um the evidence we have is that treating isolated systolic hypertension has equivalent benefits from treating mixed hypertension and the evidence in stroke is that there is no lower limit which has been proven to that you should not go below in the evidence that we have so the non the norm attentive patients in progress still benefited as much as the hypertensive patients in progress so no at the moment we would recommend treating to target there is a theoretical question in hypertension about particularly in elderly trail patients with a risk of cognitive impairment is there a problem from diastolic hypotension but all that data is observational so at the moment the randomized control evidence we have in our stroke populations is undoubtedly to treat an intensive target there isn't even some people even believe you should treat everybody regardless of their blood pressure that's we haven't gone as far as saying that and what about the ht2 inhibitors in patients with stroke and diabetes is there any any evidence that they are beneficial sorry which drug did you mention s22 inhibitors inhibitors okay um there's no good secondary prevention data at the moment that we identified for other drugs there is some coming out and i'm sure it's been formally published that i'm aware of so it was one of my end conclusions i think we do one slight problem i have is that people at the moment slightly pick a diabetic drug believing it's going to have specific benefits and haven't tested for example metformin in second prevention populations individually and i have a personal bias that we should know what the old drugs which one how good the old drugs are in specific drug classes before we go with the expensive new proprietary drug from a drug company and say this one's clearly better without having tested the one that we are using in the vast majority of our diabetic patients first of all so that so the honest answer is we don't know and i think we need ideally we'd have drug versus drug comparisons in our patients to know and we don't have that data yet thank you one question regarding statins what is your suggestion for the patients who have already ldl cholesterol levels below 0.7 or for the patients with a stroke of non-cardiambolic origin and without any sign of atelothrombotic disease sure so we don't specifically address it in the guidelines so i perhaps shouldn't give my personal response to that i i think the evidence from sparkle is that all patients were included and that when they looked at their subtypes they had equivalent benefit in their small vessel populations versus their atheroscleotic patients so the guideline covers all patients regardless of those inclusion criteria and therefore i would agree with that and i think that there was evidence if you dig into it but it's not mentioned in the guidelines so i think yes i would treat actually all my patients whether it's presenting with an ischemic cerebrovascular event or tia i would give them a statin and if they didn't achieve 1.8 i would continue to escalate treatment to try and achieve it is what the guideline sheet implies thank you one other question you suggested the use of low those [Music] anticoagulants plus an antiplatelet in patients who meet the the compass criteria if we we work in a cute soak world when is when it's the the optimal time to start this treatment so again we don't cover it in the guidelines specifically of course we have no evidence the compass data was all in patients within the chronic phase so i think in the chronic phases the right answers i think after we think there's any significant risk of that we're going to increase the risk of hemorrhagic conversion so i i personally would wait for at least two weeks for that particular treatment option because even the lack of evidence in secondary prevention and possibly longer in reality we'd be introducing it at their follow-up clinic i think in our clinics which would be a few weeks online thanks there are other questions but for the sake of time we have to move to the next guideline thanks very much [Applause]