Drugs for secondary stroke prevention

Welcome to the Australian Prescriber Podcast. Australian Prescriber, independent, peer-reviewed and free.

I'm Dhineli Perera your host for this episode. It's a pleasure to be speaking to Dr Chris Tremonti. Chris is an advanced trainee in Clinical Pharmacology at Royal Prince Alfred Hospital in Sydney. Chris neatly summarises the current evidence and best practice that needs to be considered when prescribing medications in secondary stroke prevention. Chris, welcome to the program.

Oh, hi Dhineli. It's a pleasure to be here.

Great. So Chris, I have to admit, it was kind of reassuring to see that the antiplatelet options for secondary stroke prevention haven't changed too much in the last decade or so, but obviously the combinations and the durations recommended have evolved. Let's start with aspirin. Is there an optimal dose and duration in secondary stroke prevention?

Yes. So look, it's a great question. And people have a lot of anxiety around this. Probably the most definitive meta-analysis of these came from Niu who looked at 36 RCTs around 80,000 patients that were divided into four regimens. The main, I think, take-home point was that the 75 to 150 mg dose of aspirin showed a clear benefit versus placebo, as did the 500 mg dose but that was at the risk of increased bleeding. As I said, they put them into those groups. And so I can't tell you whether or not 75 versus 150 is necessarily better, but I guess it also comes down to a bit of convenience. What are most of the brands that are out there now, and I shan't name them? Mostly around 100 mg tablets. And so that tends to be the standard dose. There are a few out there that are 300 and patients can split them into two, but we also want to do what's practical for patients. So in terms of dosing, I think that 100 mg for a patient daily, if aspirin is the agent that you're going with, is an appropriate regimen.

Now, aspirin and dipyridamole is an accepted combination.

Yes.

What were the findings in the 2006 ESPRIT, is that how you say it, ESPRIT trial?

Yes. That was the ESPRIT trial. So look, there are a few caveats with ESPRIT. So that was a randomised controlled trial of 2800 patients and the median... And so I should point out that with this study, patients were on a variety of doses of aspirin. So again, it wasn't entirely consistent. A couple of other things to point out with that study was it was unblinded and most were randomised post one month. So there were a couple of shortcomings of that ESPRIT study, but nonetheless, the outcomes were good and showed that patients that were on a combination of... typically that were on 200 mg BD [twice daily] of dipyridamole, the phosphodiesterase inhibitor, was beneficial.

I will also add though that the meta-analysis I referred to a moment ago did suggest lower rates of compliance with dipyridamole. And this is because of issues around vasodilation and headache and so forth. So there is some suggestion that it is better in the RCTs that are out there that have also studied this. I'll refer in particular to the ones from Greving, and it's got a better risk profile in terms of bleeding than aspirin alone, but by the same token that does come at this cost of this vasodilatory effect and headache and potential lack of compliance.

So, using that bleed risk that you've just touched on, is that the times that we should be using it over aspirin alone?

So that's the 2019 meta-analysis that was in Stroke by Greving which compliments well the other meta-analysis that I talked about with Niu, which highlights that both a combination of aspirin/dipyridamole as well as clopidogrel were both better than aspirin for stroke prevention, but clopidogrel was probably better than... Well, this is where you get into the nitty-gritty of numbers, where it's hard to say that clopidogrel was necessarily better than the combination of dipyridamole/aspirin, but it certainly looks like it is a bit better for bleeding risk. So this is potentially an occasion where you may look at using something like clopidogrel instead, but by the same token dipyridamole and aspirin does seem to have some benefit over aspirin for those patients that can tolerate it.

Okay. So, I guess the summary of that would be that if you would use aspirin, but in patients that might be at a significant bleed risk, for whatever reason, you'd look at either clopidogrel or aspirin and dipyridamole.

I think that's reasonable. Yeah.

So now that we've already touched on clopidogrel, what about these P2Y₁₂ inhibitors? So, that includes clopidogrel and you've touched on the advantages it has over aspirin in terms of bleed risk. Are there other advantages and disadvantages that prescribers need to consider?

Yeah, so as mentioned, I think the literature is starting to show that clopidogrel has got a good risk profile in terms of bleed. Some people worry about clopidogrel resistance. So clopidogrel itself is a prodrug that has to be converted by CYP2C19 enzyme in order to function. And there are some people out there who have a loss-of-function allele of the CYP2C19. So there was a sub-analysis of CHANCE that suggested that the benefits of clopidogrel were only in those – and apologies for the double negative here – for only in those that did not have the loss of function.

So if you cross those two out, so only for those people who only had the function of CYP2C19 functioning properly, those patients had the benefit. Whereas those in that analysis that had the loss-of-function allele didn't have the benefit. So there are some concerns around that. And look, it's not widespread practice. It's not something that's routinely done testing for that allele, but it is something to be mindful of. And look, certainly if a patient were to have a subsequent stroke on clopidogrel, I think it's not unreasonable to then change your agent.

And how was all this linked to cryptogenic strokes, which I think was…

Yeah.

You sort of linked that in your article to the clopidogrel resistance.

Yeah. So look, I mean, so cryptogenic strokes are strokes where we don't have a clear underlying cause. So I should point out that all the literature that I've been discussing so far is for strokes that are cardioembolic in nature, but not with patients with atrial fibrillation. So atrial fibrillation makes up a large proportion of patients who have strokes because they have clots in the heart that go to their brain. And then obviously having things like carotid stenosis and other cardiovascular disease contributed in large part to the others. Cryptogenic strokes. Yes, we've established that we can't find a clear cause, we've done an ultrasound of their neck, we've done maybe a Holter monitor to look for atrial fibrillation, we've monitored the patient for a period. And so then the question is how do we manage these patients?

And there's always been this suggestion that cryptogenic strokes are from atrial fibrillation we couldn't pick up; we couldn't see it on the monitor. The patient was flittering in and out of it. And for the 24 hours they were on the monitor, or the 48 hours on the monitor, they were in a sinus rhythm. So that's led some people to go then and do some studies looking at the new oral anticoagulants, so at rivaroxaban and dabigatran, and to see whether or not they should be used post-stroke.

Unfortunately those RCTs were negative. So there wasn't really any benefit. So unfortunately for cryptogenic strokes, your management is going to remain the same. If a patient doesn't have atrial fibrillation, then it's antiplatelets as mentioned. And then clopidogrel resistance, we can't say definitively what one should do if somebody has a stroke when they were already on an antiplatelet. Obviously you want to check that they're compliant. And obviously you're going to re-look for all those risk factors that were there in the first place. But what to actually do in terms of switching it around, well... I mean, there's a suggestion that perhaps we should just change anticoagulant and see how we go.

Okay. So in your article, Chris, there was a table comparing the efficacy of the antiplatelets and it appears that aspirin is most efficacious in preventing recurrent stroke, but has the highest bleed risk and the highest risk of serious vascular event, is that correct? It was... looking at the odds ratios that's kind of how I've interpreted it.

So this is a table and, if people want to, they can go and look at it both in the article and the Stroke Foundation's Australian Clinical Guidelines for Stroke Management, which is a living guideline, which is continually updated. Now, this is mostly odds ratios looking at purely aspirin and placebo and clopidogrel and placebo, and then aspirin/dipyridamole versus placebo. Now I do want to emphasise those things, because then there's all sorts of studies out there that compare aspirin with clopidogrel, aspirin versus aspirin…, so it gets really, really, really messy.

Yes. That's right.

All this is really showing us definitively is that firstly, all three agents, aspirin, clopidogrel and aspirin/dipyridamole combination, all have a benefit in preventing stroke. So they are all under one.

There is a suggestion that aspirin does have a slightly higher bleeding risk and, as you can see in this study with the odds ratio with clopidogrel, that perhaps clopidogrel odds ratio for a bleed is a little bit lower. Hence, the propensity towards this.

Does ticagrelor get a look in all of this?

The study that was done by Claiborne Johnston in, I think about in 2016, demonstrated that ticagrelor didn't appear to have any benefit over aspirin in preventing recurrent stroke. It's certainly not PBS listed or approved for stroke management. I don't believe it's TGA listed.

So your flow chart describes a scoring system for both minor stroke, so the NIHSS, and high-risk TIAs called the ABCD². Can you tell us a bit about each scoring system and where do we go to find information on these?

Yeah, so the NIHSS is a scoring system that was designed to try and risk-stratify stroke presentations. I think it's very interesting. I was reading around on this a little bit earlier and the author of it, Patrick Lyden, has written a little blurb on this – for people who are interested, you can look at MDCalc to have a look at what he said – and he talks about how it's really built for the ED to do, because neurologists actually look at these things and neurologists perhaps know a little bit more about stroke and the subtleties of stroke. And they actually often don't score them ‘correctly’ as per the scoring system, because they see so many strokes and can pick up on those subtle differences.

It's something that I've personally used. So, I was once a stroke registrar, and I would see a patient with a stroke and the consultants want to know what's their NIHSS score because it gives them some understanding of the level of severity of the stroke and the level of deficit. There are lots of caveats, so included in there is things like level of consciousness, there was some functional things and it depends on a person's previous language ability and there may have been some pre-standing deficit that has to be counted in as well. So this is where these sorts of things are not, they're not perfect. They don't replace clinical judgment and acumen, but they're just a way that you can quickly and concisely grade the patient's severity of stroke.

Similarly for TIA, they've got the ABCD² score, which was actually created by one of the authors of one of the studies I've just mentioned moments ago, Claiborne Johnston. And basically, again, it's a way to look at the risk factors of a person who's had a TIA and their likelihood of having another TIA down the track. And when we look at a lot of the literature, when we look at the studies that have come out, and that I've talked a lot about in this article, most of them are looking at patients that have been risk-scored by these systems. So they use these systems to... They don't usually include patients who've had severe strokes. They usually include those who've had a severe TIA or a more mild stroke by these scores.

Okay. Well, that's good to know. And especially if we're going to start using them ourselves, or as you said, ED physicians might be using them more often. It's good to have a little bit of an idea of some caveats around it too.

Absolutely.

So, Chris, can you tell us a bit about the findings from the CHANCE and POINT trials? How long should dual antiplatelets continue for?

So, CHANCE and POINT were two studies where they were looking at combination therapies of clopidogrel and aspirin versus single-agent therapy in the treatment of patients who had either a high-risk TIA or a minor ischaemic stroke. So to come back to those scoring scores, that's an ABCD² score of over 4 or NIHSS score of 3 or less. And basically the evidence has shown that, from both of these two studies that have been subsequently put into a meta-analysis, that there is a benefit, but the benefit is in the acute phase and it's not something that's longstanding.

So at the moment, the recommendation for patients who've had a stroke that falls into those two categories is that they should be on them for three weeks. That's as per the Australian Stroke Foundation's Guidelines. POINT went out to 90 days and showed that there was some benefit for patients in that first 90 days. And so the question of what to do for that three-weeks to three-month period is still a little bit grey. There's certainly no evidence for beyond three months. So beyond that 90-day period.

So moving on, the evidence for anticoagulants now, so not antiplatelets, in AF to prevent secondary stroke is unequivocal. The pros and cons of the options is actually in the April [2021] issue of Australian Prescriber. And I actually did the podcast for that one too. So if anyone's interested, they could go back and have a listen to that. So what about if they're on an antiplatelet to start with, and they’re not on an anticoagulant, then they have a stroke, and then they're newly commenced on that anticoagulant, what happens to the antiplatelet after that stroke?

If a person is on an antiplatelet and they have a stroke, and they're discovered to have atrial fibrillation, then obviously we want to put them on to one of the new oral anticoagulants. And ideally we do want to stop the antiplatelet. Now, the challenge is obviously what was the reason that they were on their antiplatelet and really that then becomes a conversation between the neurologist and the cardiologist as to whether or not it's necessary, because those are the two main reasons that people are on them. People often take antiplatelets because they've had a myocardial infarction and coronary stenting. In terms of risk for patients who've had a stent and then have atrial fibrillation, it really needs to be a conversation between those two, because both are going to be making the case that they need to be on both. But where possible, obviously we want to try and get rid of the antiplatelet if we can.

Yes. And let's say they were on the antiplatelet for say a TIA previously, and then they have a stroke and that's the kind of situation where it'd be an easy drop of the antiplatelet.

Absolutely. Anticoagulant, remove the antiplatelet.

Yeah. Perfect. And when it comes to blood pressure control, which agents are recommended and what systolic blood pressure should be targeted in this population?

Yeah, sure. So, in patients who've had a stroke, and these are fairly consistent for most cardiovascular complications and risk factors, the first-line agents are ACE inhibitors, calcium channel blockers, and thiazide diuretics after a stroke. But of course you want to individualise that for each patient. So some patients don't like calcium channel blockers because it causes leg swelling. Some patients will have renal impairment and can't use an ACE inhibitor. Some patients may have issues with hyponatraemia and so thiazide diuretics, or they may not have good mobility and thus a diuretic is not a good choice. So, those are all some considerations to take into account. Adherence to diuretics in terms of antihypertensive compliance has been shown to be a bit worse. So again, if you've got a patient where they get continually high blood pressure and they're on a thiazide diuretic or any other diuretic, and then it's certainly something to consider.

In terms of the targets at the moment, so 140 mmHg is the target at the moment. There is some suggestion that a target of below 130 may offer a small benefit for patients who've had a lacunar infarct, but at the same time, this comes at a bit of a risk of unsteadiness and especially in patients who are a bit older. So this of course is just talking purely about stroke. If they've got other complications like renal disease or anything like that, then their target may be different to this.

And then the cholesterol is the other thing that we want to target for secondary stroke prevention. And I've heard some patients being concerned about their cholesterol being too low. What is the evidence around target LDL levels in this population?

Well, this is a wonderful lesson in the beauty of peer review. So when I wrote this article, I had missed the very recent article that had come out about targeting cholesterol by Amarenco where they actually did an RCT looking at 2800 patients that were enrolled and followed for a median of about three and a half years, where they actually divided the groups into tight controls. So under 1.8 [mmol/L] and then a different group that was not quite as tight control. And the outcomes showed that patients with an LDL level of less than 1.8 had better outcomes than the patients that were not as strict as a control.

The question then becomes obviously, what do we do to get that down? So statins are still the preferred first-line agent. And then, and we want to try where possible, even in patients that have a normal cholesterol that have had a stroke, patients should be on statin therapy, regardless. Obviously some patients don't tolerate statins well because of the complications for that, the myopathies and so forth, but we should still try our best to have a patient on a statin, even if it's at a lower dose.

And remembering that that is actually a statin-specific side effect. So I think flicking around between some of the others within the same class is worth a go.

And so then, in terms of second-line agent, ezetimibe is probably the best next-line agent, but it's still unclear as to... This is mostly based on studies that have been done for acute coronary syndrome, where patients were trying to get their cholesterol lower and they've already maxed out on the statin. And so then we need another agent. So usually ezetimibe is the next agent. We don't know if ezetimibe works well by itself, there’re patients who might not be able to tolerate any of the statins. And of course, again, ezetimibe has its own issues in terms of myalgias and headaches and so forth that need to be explained to the patient before they start on it.

Okay. Excellent. And then finally, Chris, I think it's always useful to find out where your top online source for updated guidelines and treatment recommendations are for this topic. Where should we go for more information?

Yes. So, I recommend the Australian Stroke Foundation's Clinical Guidelines, which is a living document that is continually changing and updating in order to provide best management, not just around the pharmacotherapy of secondary stroke prevention, but around a number of different things with regards to stroke management in terms of non-pharmacological management and long-term outcomes and so forth as well. So I would direct people to look at those and they’re continually being updated with, as new evidence comes to light, which as you can see in this field is it's a common condition with lots of research and things are continually changing.

Yeah. Which is a good thing.

Oh, well, it's not good there's lots of people having strokes, but it's certainly good that we've got a good research base on which to work with.

Absolutely. Well, that's unfortunately all the time we've got for this episode. Thank you so much for joining us today, Chris.

No. Thanks for having me. It was a pleasure.

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The views of the hosts and guests on the Podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Dhineli Perera and thanks for joining us on the Australian Prescriber Podcast.