Antiplatelet Therapy to Prevent Stroke: Where does Aspirin fit in?


Antiplatelet Therapy to Prevent Stroke:
Where does Aspirin fit in?

Chris Cannon, MD: Hello. I’m Chris Cannon, a cardiologist at Brigham And Women’s Hospital in Boston and professor at Harvard Medical School. Welcome to this program titled, “Antiplatelet Therapy to Prevent Stroke: Where Does Aspirin Fit In?” Joining me today is Professor Graeme Hankey who’s a professor of neurology at the University of Western Australia and a consultant neurologist at Sir Charles Gairdner Hospital in Perth, Australia. So welcome, Graeme.

Graeme Hankey, MD, PhD: Thank you, Chris.

Dr. Cannon: Well, stroke is something that we think about in cardiology as really a dreaded complication, and one that can occur in the acute setting. But then primary prevention of stroke is obviously something that we think about in our cardiovascular patients. It really becomes a key thing for us to focus in on. In this program, we’ll try and discuss some of the details of how to best identify patients at risk, look at some of the evidence supporting antiplatelet therapy and aspirin in particular, on both the primary and secondary prevention of stroke, as well as some of the new data that are changing some of the guideline recommendations. We’ll start out. Graeme, can you tell us a little bit about the global burden of stroke?

Professor Hankey: Thank you, Chris. Well, the global burden of stroke is substantial. In 2016, there were 13.7 million first strokes or about 2 in every 1,000 people in the world had a stroke in that year. They were added to a pool of about 80 million prevalent survivors of stroke. About 1 in a 100 people in the world have had a stroke and are survivors of it. In the Global Burden of Disease Study in 2016, it was estimated that the lifetime risk of stroke amongst adults aged 25 years and older is 25%. So 1 in 4 adults can expect to have a stroke in their life, about 1 in 5 or 6 will have an ischemic stroke, and about 1 in 12 will have a hemorrhagic stroke.

Dr. Cannon: Well, that is just amazing and so eye-opening to see the global burden. Stroke, I guess, is a multi-factorial or multi-etiology disease. We’ll next cover some of the different causes of ischemic stroke and hemorrhagic stroke, but then focus on what strategies we can adopt both locally and globally, to try and reduce this stroke risk. And that can range from acute treatment of stroke to all the way to primary prevention. Graeme, do you want to cover some of the different causes?

Professor Hankey: Yes. Well, a stroke has come into our vernacular. Some of us use it to describe a sporting stroke or a swimming stroke or a stroke of luck. But a stroke is actually a loss of function of a particular part of the body due to a loss of function of a particular part of the brain due to a blocked vessel, an ischemic stroke, or a burst vessel. And there’s about more than 200 causes of ischemic stroke, and many causes of hemorrhagic stroke. The most common causes of ischemic stroke are intracranial small vessel disease, like hypertensive small vessel disease that causes lacunar strokes in about 1 in 6 patients with ischemic stroke. But more commonly, blocked arteries in the brain are caused by emboli that have originated from a more proximal source in the intracranial or extracranial large carotid or vertebral arteries, or aortic arch, or the heart. As our population is getting older, we’re seeing a lot more atrial fibrillation. Cardiac disease is overtaking arterial disease as a major cause of ischemic stroke. About 75 to 85% of strokes are ischemic, depending on different populations. Most strokes can be attributable to 10 modifiable risk factors. The major risk factor for stroke is hypertension, because hypertension or high blood pressure predisposes to most of the major etiological subtypes of stroke. As you can see, atrial fibrillation and the other horseman of the apocalypse of stroke are traditionally diabetes, high lipids that emerge in the lack of physical activity, high waist-to-hip ratio, alcohol. And so these are all potentially modifiable. We use these factors or have used these factors traditionally, to try and determine the absolute risk of stroke among people who haven’t had a stroke. Each seems to have additive value, but there are some limitations of these risk stratification tools, particularly the ones that were derived from older cohorts when applied to new populations who are perhaps managed medically with better medical therapies. Equations such as the Pooled Cohort Equation whilst validated in some populations, does tend to overestimate risk in other populations or underestimated in some. The discrimination of these prognostic tools is not that great. That’s why we’ve come to try and identify how the strategies of predicting risks that might value-add to traditional risk factors, such as further history from the family history of premature vascular disease. Or the race, blood tests, not just the LDL cholesterol, but the lipoprotein little A, also triglycerides and APO B, and high-sensitivity CRP. And of course, renal function is very important as a predictor of not just ischemic events, but bleeding events. Furthermore, imaging has become very important. Trying to image the arteries from coronary artery calcification. Carotid artery, not just stenosis, but actually the plaques. We can also look at the end organ, the brain. On MRI now, we get very good sensitive imaging of silent brain infarction, white matter hyperintensities due to clogging up of the small, little vessels, and also cerebral microbleeds, an indicator of a high risk of ischemic vascular events, as well as hemorrhagic. And therefore, not necessarily a preclusion to antiplatelet therapy.

Dr. Cannon: Well, that’s a tremendous review. Unfortunately, 70% of the patients are first-ever strokes, and then the remaining 30% of recurrent strokes. But finding those with the first stroke at risk of that, is really key because it’s 70%. Across cardiology and medicine in general, the notion of risk stratification to target preventive therapies has really grown. And including, I think in targeting aspirin, even in general primary prevention. As we look at the data for aspirin, we’ve had a wonderful flurry of big trials to help guide treatment, and even some new ones coming, that really cover the spectrum of primary prevention to secondary prevention, and that in-between group of the imaged disease. You were talking about the carotids and identifying some plaque. Not just stenosis, but if there’s plaque there, that essentially is a person with image disease. And it’s more in my mind, like a secondary prevention patient. But in primary prevention, we had 3 large trials and then meta-analysis of these, ASCEND, ARRIVE, and ASPREE, that really helped identify in different populations that ASCEND was in diabetes, and ARRIVE a more general population, but ASPREE in elderly patients. That, I think, was very instructive in identifying and matching this notion of having enough risk to then come in with a preventive strategy. For secondary prevention, there’s aspirin alone. And that’s been the standard for years, largely from the acute treatment trials, the notion of dual antiplatelet therapy. But that had been looked at even in the MATCH trial with clopidogrel years ago. And there’s the lack of data in the group that simply imaged vascular disease, but growing interest, I think in that group. And then, where does anticoagulation fit into this primary prevention?

Obviously, in atrial fibrillation, that’s primary therapy, but for the non-atrial fibrillation patients, and then the dose of aspirin, we’ll soon have some randomized data come in, which will be exciting.

Looking for first, anchoring the treatment with aspirin, and this is a relatively recent meta-analysis, looking at the use of aspirin in primary prevention. You can see that for the composite cardiovascular death, MI, and stroke, a highly significant reduction in events. It’s just a trend, but a favorable trend on mortality and cardiovascular mortality. That’s often the case in primary prevention studies, because they’re generally lower-risk patients. But the flip side of every antithrombotic agent is increased risk of bleeding. And that certainly has been seen both for major bleeding and intercranial bleeding, and the subset of GI bleeding. The takeaway here in absolute terms to us, that if you looked at for primary prevention use of aspirin, it would lower the risk of stroke, MI or cardiovascular death by an absolute 0.38%. But then increase the risk of bleeding by 0.47%. Interestingly, almost a 1-to-1 trade for the benefit versus bleeding. But many of us will think, “Gee, it’s worse to have a stroke or an MI than to have often a reversible major bleed.” But that’s the ever-present balance where then you try and incorporate the risk stratification to target those at higher risk, where that benefit may be greater than the risk.

With that as a basis, I think then turning more to other treatments, a lot of them have come from the acute management where we think about dual antiplatelet therapy. Certainly, in cardiology, we’ve tried several different types of dual antiplatelet therapy. And that’s now the case even in stroke management. Maybe I’ll let you cover some of the acute treatments.

Professor Hankey: Well, thank you, Chris. Well, when patients present with an acute ischemic stroke and a CT scan doesn’t show any bleeding, of course, one of the major revolutionary treatments is revascularization therapy by thrombolysis with tissue plasminogen activator in the first 4.5 to up to 9 hours, and endovascular thrombectomy for people with a large-arter occlusion, which is dramatically effective in saving about 1 in 3 patients from death and disability with 3D revascularization. But another reason for patients with acute ischemic stroke to be admitted urgently to hospital and to be assessed urgently, is that usually, there’s an underlying cause, that underlying vulnerable plaque in the arterial system that is prone to re-rupture or re-thromboembolize. And so, patients with just transient ischemic attacks who have recovered, or mild ischemic strokes, who may not necessarily need thrombolysis or endovascular therapy still have to be taken very seriously. As you can see from the Oxford study, a community based study in Oxford, those people with TIA and minor ischemic stroke had a 5% risk of a recurrent stroke in the next 2 days, and a 10% risk within a week. We need not just try and prevent plaque progression, but we want to instill appropriate thromboprophylactic. Aspirin is an incredibly good antithrombotic treatment. As you can see from a pooled analysis of patients with acute ischemic stroke in the International Stroke Trial and the Chinese Diaspora Stroke Trial, as well as other trials, compared to no aspirin, aspirin dramatically reduces the risk of recurrent stroke within the first 6 to 12 weeks, if it is started within the first 48 hours of onset. And it doesn’t just reduce non-disabling ischemic strokes, recurrent ones, but also disabling recurrent ischemic stroke. Aspirin is the pillar or the foundation of our thromboprophylactic regime in acute TIA and mild-ischemic stroke. No patient should leave the emergency department without it. Secondly, aspirin perhaps reduces the risk from about 15% at 1-month to about 9%. But adding clopidogrel to aspirin can further reduce the rate of recurrent ischemic stroke from about 9% at 30 days to about 6%. Whereas, it only causes an increase in bleeding of about another 0.2%. The caveat of these 3 trials of adding clopidogrel to aspirin in 10,000 patients with ischemic stroke or TIA, was that they’re only mild ischemic strokes or TIAs. So, they didn’t have a large area of brain infarction that is at risk of hemorrhagic transformation. These trials of adding clopidogrel to aspirin is only generalizable to patients seen within the first 24 hours or so, and who have a TIA they’ve recovered, or their National Institute of Health Stroke Scale score is less than 5. That is, they’ve got a mild deficit. Because some people don’t respond to clopidogrel, about 1 in 4 Caucasians and up to 60% of Asians don’t metabolize the inactive clopidogrel drug to the active metabolite. There’s an opportunity for improved secondary prevention with dual antiplatelet therapy by using a direct P2Y12 inhibitor that is active, like ticagrelor. The THALES trial just published this year, compared aspirin with adding ticagrelor to aspirin for 30 days in 11,000 patients with TIA or mild to-moderate acute non-cardiac embolic ischemic stroke. And again, the results were very similar to the clopidogrel assessment trials, with about a 20 to 30% reduction in recurrent stroke from about 6.5% to 5% at 30 days, with a small excess risk of bleeding of about 4 per 1,000. Generally, we use aspirin as an early secondary prevention, and we supplement it with clopidogrel, or ticagrelor for those with mild ischemic strokes. Another really burning question is, what about the people with cryptogenic ischemic stroke? They have an embolic stroke of undetermined source, and we’re not sure what the cause is. The NAVIGATE-ESUS trial showed there was no significant reduction in major vascular events and recurrent stroke over about 11 months of follow-up. But there was an excess of bleeding with rivaroxaban in that first 11 months. The trial was halted early similarly, the RESPECT-ESUS trial, again, there was no significant difference in recurrent stroke, but there actually wasn’t much excessive bleeding either with dabigatran. And you can see the curve start to diverge after a longer period of follow-up in the second year, but dabigatran was not shown to be statistically significantly better than aspirin for embolic stroke of undetermined source. Aspirin still has a major role in all subtypes of non-cardioembolic ischemic stroke.

Dr Cannon: Terrific. Well, this has been a really neat overview. Of course, we then want to think about, how does this impact our guidelines? And certainly one big change in the guidelines came in 2019 in the ACC/AHA guidelines for primary prevention, that incorporated those primary prevention aspirin trials, and notably the study of patients aged 70 or older, the ASPREE trial, not showing benefit. The guidelines shifted to say that we shouldn’t just have a blanket recommendation for anyone, that they should take aspirin for primary prevention, but to really incorporate risk and not just age. Do you want to touch on some of the new things in the stroke guidelines?

Professor Hankey: Thank you, Chris. Regarding the use of aspirin, first, has the person had symptomatic cardiovascular or cerebrovascular disease, and it’s ischemic for which aspirin is indicated? If they have atrial fibrillation,anticoagulation is indicated. But for the vast majority of people in the primary care population, we used to think that aspirin should be in the drinking water, that it only had very mild risks. And it probably had a modest effect on everyone that was beneficial. I think these 3 recent trials of aspirin versus no aspirin in primary stroke prevention and vascular prevention in healthy, elderly people, has given us caution and shown that amongst this population who are only at low risk of future ischemic cardiovascular events, they still have a risk of bleeding. Aspirin can increase that risk of bleeding. The risks of bleeding can almost offset the benefits, and so there can be no net benefit. So it’s focused our attention on being more selective in primary prevention, and using not just traditional risk factors, but also risk-enhancing biomarkers to try and more accurately ascertain risk of ischemic vascular events, as well as the risk of bleeding.

Dr Cannon: Terrific. Well, this has been just a wonderful discussion and overview of all these new data on such an important and prevalent topic. We want to thank you, the audience, for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. And thank you, Graeme, so much for a wonderful program.