Disabling Stroke Reduced With Ticagrelor After Minor Stroke, TIA

Additional results from the THALES trial have shown that one month's dual antiplatelet therapy with ticagrelor (Brilinta; Astra Zeneca) plus aspirin is associated with a reduction in disabling stroke compared with aspirin alone in patients with minor stroke or high-risk transient ischemic attack (TIA).

Primary results of the THALES trial, published earlier this year in the New England Journal of Medicine (NEJM), showed a reduction in the primary endpoint of stroke or death within 30 days with the combination of ticagrelor plus aspirin versus aspirin alone, although this was accompanied by an increase in bleeding.  

In terms of risk/benefit, the main results showed that for every 1000 patients treatment with ticagrelor on top of aspirin would prevent 11 strokes or deaths at the cost of four severe hemorrhages.

The current exploratory analysis, which focuses on the severity of the strokes occurring in the trial, was published online in JAMA Neurology on November 7 to coincide with its presentation at the European Stroke Organisation-World Stroke Organization  (ESO-WSO) Conference 2020.

Dr Clay Johnston

Results showed that, compared with aspirin alone, ticagrelor plus aspirin significantly reduced the 30-day risk for disabling stroke or death (4.0% versus 4.7%), and the total disability burden (the shift analysis of the distribution of modified Rankin scale) following subsequent ischemic stroke was reduced by a significant 23%.

"This new information on disabling stroke underlines the importance of getting patients on dual antiplatelet therapy quickly after a TIA or mild stroke," principal investigator of the THALES trial, Clay Johnston, MD, PhD, told Medscape Medical News.

Johnston, who is dean of Dell Medical School at The University of Texas at Austin, added: "It's reassuring that ticagrelor has this effect, which was pretty robust. An accompanying editorial to the THALES publication in the NEJM incorrectly stated that ticagrelor did not reduce risk of disabling stroke, so it is good to be able to correct that misconception with this new data."

Dr Pierre Amarenco

Lead author of the exploratory analysis, Pierre Amarenco, MD, professor of neurology at Bichat University Hospital, Paris, France, added: "The main results showed that ticagrelor on top of aspirin reduced stroke but now we have new information showing reduction in disabling stroke. Obviously, these are most important types of stroke to prevent. These are the strokes that will impact patients functionally."

The THALES trial included 11,016 patients with a noncardioembolic, nonsevere ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 5) or high-risk TIA, of whom 10,803 had modified Rankin Scale (mRS) functional score recorded at 30 days. 

They were randomized within 24 hours of symptom onset to ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for 1 month) or placebo. All patients received aspirin (300 mg to 325 mg on day 1 followed by 75 mg to 100 mg daily for 1 month).

In the new analysis, time to occurrence of disabling stroke (mRS greater than 1) or death within 30 days occurred in 221 of 5511 patients (4.0%) randomized to ticagrelor and in 260 of 5478 patients (4.7%) randomized to placebo (hazard ratio, 0.83; P = .04).

The ordinal analysis of mRS in patients with recurrent stroke showed a shift of the disability burden following a recurrent ischemic stroke in favor of ticagrelor (odds ratio, 0.77; P = .002).

Factors associated with disability were baseline NIHSS score of 4 to 5, ipsilateral stenosis of at least 30%, Asian race/ethnicity, older age, and higher systolic blood pressure.

Asked how the current results compared with observations reported in the main NEJM paper of similar incidences of disability (mRS > 1) in the two groups, Johnston explained that the result in the original paper looked at disability in the overall population, not just those who went on to have a stroke during follow-up. 

"The problem with looking at overall disability is that most of it is actually from the index stroke (the one that led to the patient being enrolled in the trial). That creates a lot of noise that overwhelms the benefit in reducing disability due to new stroke, the thing we really care about and the subject of the new paper," he commented.

Ticagrelor or Clopidogrel?

Ticagrelor now becomes the second antiplatelet agent to have shown benefits on top of aspirin in the minor stroke and high-risk TIA population. Clopidogrel also showed a reduction in major ischemic events in the POINT trial as well as in the Chinese CHANCE trial in similar populations.

Amarenco pointed out, however, that until now the only treatment that has been shown to reduce disabling stroke in the minor stroke/high risk TIA population in a single trial is aspirin.  

"The CHANCE and POINT trials of clopidogrel did not show a reduction in disabling stroke individually but this was observed when the trials were combined," he noted. 

"Clinicians will now have to choose between ticagrelor and clopidogrel. We don't have a head to head comparison yet but ticagrelor is effective in all patients whereas clopidogrel may not be as effective in the large subgroup of patients who carry the loss of function gene which make up about 20% of the western population and about 40% of the Asian population," he said. 

"It is very important in the acute phase of stroke to know that the antiplatelet drug is immediately effective as the risk of a recurrent event is highest in the first few hours and days."

Amarenco acknowledged that some hospitals may favor clopidogrel because of cost, as it is available generically so is much cheaper than ticagrelor. "But we are only talking about 30 days of treatment, so cost is not too much of an issue," he pointed out.  

The US Food and Drug Administration (FDA) has just last week approved use of ticagrelor in this indication on the basis of the THALES study.

"It is great news that vascular neurologists now have a new player for reducing future stroke in these patients," Amarenco said. Clopidogrel is not approved for this indication but is recommended in American Heart Association/American Stroke Association guidelines, he added.  

Johnston, who was also the lead investigator of the POINT trial with clopidogrel, suggested that it is more important to get patients on dual antiplatelet therapy rather than worrying too much about which agent to use.

"I think we can use aspirin plus either ticagrelor or clopidogrel. The effect on disabling stroke was not significant in POINT but it did reach significance in a meta-analysis combining POINT and CHANCE," he noted.

He says that choosing between ticagrelor and clopidogrel is tricky without head-to-head data. "Differences in the studied populations makes direct comparison of the trials unwise," he stressed.

Johnston points out that neither of the clopidogrel trials included moderate strokes (NIHSS scores of 4 and 5) in their study population. "We only have data on ticagrelor for this important group, which accounted for 30% of the THALES study population," he noted.

"Some people are concerned about the limited efficacy of clopidogrel in large subgroups of patients who do not metabolize it to its active form, but on the flip side, clopidogrel is cheaper (though a 21- to 30-day course probably isn't that costly) and has more data in combination aspirin," he added.

Johnston said that the approval of ticagrelor for this new indication was "reassuring," and "provides some air cover for practitioners given the risks of hemorrhage." He added: "We didn't bother with an FDA submission after POINT because it was an NIH-sponsored trial. The drug company normally prioritizes regulatory approvals for marketing purposes but their interests were limited because clopidogrel has exceeded its patent life."

Cost-utility analyses are not yet available, but Johnston noted: "I suspect both drugs will have substantial benefits and be cost saving. Stroke is expensive, particularly disabling stroke."

Johnston says that the more important message is: "Get these people on dual antiplatelet therapy as soon as possible. Too many patients are not getting the right treatment immediately after symptom onset. We have lots of work to do here."

Commenting for Medscape Medical News, J. David Spence, MD, professor of neurology at the Robarts Research Institute, London, Ontario, Canada, who was not involved in the THALES trial, said this new analysis provided useful and important information that should reassure and encourage clinicians to use dual antiplatelet therapy in this patient population.

He points out that the shift analysis gives the most clinically relevant results.

"While the number of patients with a disabling stroke defined as an mRS > 1 is lower in the ticagrelor group, I am much more interested in the effect on more severe disability levels — those with an mRS score of 3 or more. Those are the disabilities that we really want to prevent. And from examining the shift analysis distribution, we can see that these more severe disabilities are being reduced with ticagrelor."

Spence believes the benefit/risk ratio of dual antiplatelet therapy could be further improved by better control of blood pressure. "The absolute risk of severe hemorrhage was low in this study, but in my view, most of this could have been prevented by better control of hypertension, as 20 of the 28 severe hemorrhages in the ticagrelor group were intracranial bleeds which can be significantly reduced by good blood pressure control.
"In my view, the increased risk of hemorrhage with dual antiplatelet therapy should not be regarded as inevitable; it can be virtually eliminated with better medical care," he stated.

Another outside commentator, Peter Rothwell, MD, PhD, FRCP, professor of neurology, University of Oxford, United Kingdom, also believes this is an important paper.

"The main NEJM report presented the data on overall disability, but did not present a clear analysis of the effect of ticagrelor plus aspirin on disabling recurrent stroke, but disability in all patients is mainly determined by non-vascular pre-morbid disability and by the effects of the initial pre-randomization stroke. It was highly unlikely that ticagrelor plus aspirin would change these pre-trial factors. The only thing that treatment could change was the severity of any post-treatment recurrent stroke, which it did," he told Medscape Medical News.

"There is evidence that aspirin plus clopidogrel has the same effect on disabling recurrent stroke. So we now know that ticagrelor plus aspirin also has this effect, which informs consideration of the relative merits of the two treatment strategies," Rothwell added.

The THALES trial was sponsored by Astra Zeneca. Johnston reports support from Sanofi and AstraZeneca outside the submitted work. Amarenco reports grants and personal fees from AstraZeneca and Bristol-Myers Squibb during the conduct of the study. 

European Stroke Organisation-World Stroke Organization (ESO-WSO) Conference 2020. Presented November 7, 2020.

JAMA Neurol. 2020. Published online November 7, 2020. Full text. 

For more Medscape Neurology news, join us on Facebook and Twitter.