In this video, S. Claiborne “Clay” Johnston, M.D., Ph.D, Special Assistant to the President and Provost; Professor, Department of Neurology, Dell Medical School, University of Texas at Austin, Austin, Texas, discusses his presentation at the 146^th Annual Meeting of the American Neurological Association titled “Insights into Using Dual Antiplatelet Therapy in Patients with Acute Ischemic Stroke and Transient Ischemic Attack.”

Read the Transcript:

Hi. I'm Clay Johnston. I'm a Professor of Neurology at the Dell Medical School of University of Texas at Austin. I'm going to give a recap of a presentation that I gave at the American Neurological Association meeting, on clopidogrel plus aspirin for acute ischemic stroke or TIA.

I'm going to talk a little bit more about dual antiplatelet therapy, not just with clopidogrel but also ticagrelor.

This has become a confusing area, thanks to a bunch of recent clinical trials. I've been fortunate to be involved with them. I should mention that, as leader of one of these trials, I received support from AstraZeneca, who makes ticagrelor.

Part of the confusion is that we've looked at the combination of clopidogrel and aspirin before. We've had these big randomized trials from before. MATCH is an example, SPS3 is another example. Different populations. Not including that early period after a TIA or a stroke, but including a later period.

The combination, maybe it reduces the risk of stroke a little, but it increases the risk of hemorrhage. Those trials have been negative. In the long-term, it's pretty clear, the combination of clopidogrel and aspirin doesn't work. It's just not worth the risk.

What was going on in those trials was, they were not including that very early risk period. That is a critical risk period, because you look out at a year, 40 percent of events will have occurred in the first two days after a TIA or minor stroke. That's an important period to look at.

New trials have evaluated that space. Two, the two biggest trials in that space of dual antiplatelet therapy have been CHANCE and POINT. I was involved in both those trials.

Now let me just quickly say what they showed. Both those trials enrolled people after a high-risk TIA, so using that ABCD^2 score, looking at higher scores on the ABCD^2 score, or a minor ischemic stroke, so NIH Stroke Scale scores up to and including three.

They had to be seen within 24 hours...Actually, in POINT, in our trial, within 12 hours. Anyway, treated very abruptly, quickly, with a load of clopidogrel, and then out for at least 21 days, in POINT, for 90 days. Looking at recurrent ischemic events, slightly different outcomes in the two, but it's not that relevant.

What those two trials found was that the combination works. It actually works quite well. The hazard ratios in CHANCE were 0.68, which is huge. In POINT, it was 0.75 for their primary efficacy outcomes.

Both were pretty well tolerated. In CHANCE, there was no real increase in hemorrhage. In POINT, there was an increase in major hemorrhage, but most of those were GI hemorrhages. Clearly benefit better than risk.

They work. People should be using dual antiplatelet therapy. It's probably good enough to treat for 21-30 days. The subgroup analyses from the two trials suggest that 21 days is probably optimal treatment to maximize ischemic benefit and reduce the risk of hemorrhage.

The guidelines now do recommend as a 1A recommendation, clopidogrel and aspirin, in that patient population -- high-risk TIA, minor ischemic stroke.

What Greg Albers presented after my presentation was, "...but what about ticagrelor?" The most recent trial was the THALES trial. I was the principal investigator of that trial. It looked at ticagrelor and aspirin versus aspirin alone. It was also a positive trial.

There are reasons to think ticagrelor might be better because of imperfect metabolism of clopidogrel to its active form. Some genetic differences in cytochrome P450, the CYP2C19 pathway, that are relevant for clopidogrel but not relevant for ticagrelor. There are reasons to think it might work better.

In the THALES trial, it didn't work any better, although obviously it's a very different population, very different era, but did reduce ischemic events  at some cost of hemorrhage. Then, more recent data suggests it's about 4:1 reduction in ischemic events to an increase in major, very severe, persistent hemorrhage events.

That gives you a summary. The key is, get people on dual antiplatelet therapy. Two trials support clopidogrel, one trial supports ticagrelor. The indirect comparisons are probably not wise. How to choose between the two is complex.

The upcoming CHANCE-2 trial will bring more information into that by studying the group that doesn't metabolize clopidogrel well to its active form, and then randomizing that group to ticagrelor versus clopidogrel, will get an answer to whether it's important to direct a certain subgroup anyway, to ticagrelor, as opposed to clopidogrel.

That's up and coming. In the mean time, please get patients on dual antiplatelet therapy that meet the criteria for these trials. It's definitely underutilized currently.