Ticagrelor Beneficial for Moderate Stroke: New THALES Analysis

July 16, 2021

For patients with a moderate-size stroke, benefit from ticagrelor plus aspirin was the same as for patients with minor stroke, a new exploratory analysis of the Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial shows.

Senior THALES investigator Claiborne Johnston, MD, dean, Dell Medical School of the University of Texas at Austin, told Medscape Medical News that two previous trials of dual antiplatelet therapy for stroke patients have shown benefits of clopidogrel plus aspirin for patents with minor stroke (National Institutes of Health Stroke Scale [NIHSS] score, 0–3). The THALES trial included both patients with minor stroke and patients with moderate stroke (NIHSS, 0–5), which was a broader cohort.

"The THALES trial showed ticagrelor plus aspirin vs aspirin alone reduced vascular events with a small increase in hemorrhage risk in the overall population included. The question we looked at in this analysis is whether ticagrelor was also of benefit in the moderate-stroke patients (NIHSS, 4–5) as well as the minor-stroke patients," Johnston said.

The findings were published online July 9 in JAMA Neurology.

Bleeding Risk?

There has been concern that dual antiplatelet therapy may increase hemorrhage risk, particularly intracranial hemorrhage caused by a bleed into the initial infarction, among patients with larger stroke, said Johnston.

The current analysis showed that for patients with higher NIHSS scores (4 and 5), the benefit from ticagrelor plus aspirin vs aspirin alone was the same as for patients with lower NIHSS scores.

"There was no difference in efficacy or risk of bleeding between the higher- and lower-risk patients, with benefits outweighing risk in patients with both moderate and minor stroke," he noted.

At present, dual antiplatelet therapy is not recommended for patients with larger infarctions (NIHSS scores of ≥6) because of concerns about bleeding. THALES is the first stroke trial to include patients with NIHSS scores of 4 or 5 in a dual antiplatelet therapy trial, Johnston added.

The THALES trial compared ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily on days 2 to 30) with placebo within 24 hours after onset of stroke symptoms. All patients received aspirin 300–325 mg on day 1 followed by aspirin 75–100 mg daily on days 2 to 30.

Patients were observed for 30 additional days. The primary outcome was time to stroke or death within 30 days. The primary safety outcome was time to severe bleeding.

The current analysis compared patients with moderate stroke (baseline NIHSS score, 4 or 5) with patients with minor stroke (NIHSS score, 0–3). A total of 9983 patients with stroke were included; 3312 patients had moderate stroke, and 6671 had minor stroke.

Results showed that the benefits of ticagrelor were similar for both moderate-stroke and minor-stroke patents.

The observed primary outcome event rate for patients with moderate stroke was 7.6% for those in the ticagrelor group and 9.1% for those in the placebo group (hazard ratio, 0.84; 95% CI, 0.66 – 1.06). The primary outcome event rate for patients with less severe stroke was 4.7% for those in the ticagrelor group and 5.7% for those in the placebo group (hazard ratio, 0.82; 95% CI, 0.66 – 1.01). The P value for interaction was .88.

Severe bleeding occurred in eight patients (0.5%) in the ticagrelor group and in four patients (0.2%) in the placebo group among those with moderate stroke, compared with 16 patients (0.5%) and three patients (0.1%), respectively, among those with minor severe stroke (P for interaction = .26).

Because of the small increased risk for severe bleeding shown in the overall THALES trial, there has been much discussion on whether the benefit outweighs the risk for all patients.

Undertreated Population

Johnston said, "While this hasn’t fully been resolved yet, we haven’t found a subgroup who shouldn’t be treated with ticagrelor.

"This analysis now provides evidence supporting ticagrelor in these patients with moderate stroke. This was the group for which there was the most concern over bleeding risk, but even in this group, ticagrelor looks beneficial," he added.

Ticagrelor now becomes the only antiplatelet to have shown benefit when added to aspirin for patents with moderate stroke. For patients with minor stroke (NIHSS, 0–3), both clopidogrel and ticagrelor have shown benefit.

Asked how to choose between these two drugs for patients with minor stroke, Johnston said this question is still unresolved at present.

"Clopidogrel can be influenced by genetic differences that may compromise its efficacy, but we need more information on that," he noted.

The CHANCE-2 trial is due to report soon on this issue. That trial is comparing clopidogrel with ticagrelor for patients who carry the clopidogrel loss-of-effectiveness gene.

"The trouble is, we don’t know if patients carry this gene when they need to be treated immediately after having a stroke. The genetic tests take time, but we need to start treatment straight away," Johnston explained.

"On the other hand, the clopidogrel data have been out for longer, there are two trails available (CHANCE and POINT), and the guidelines reflect that with a stronger level of evidence. So more clinicians probably use clopidogrel for these reasons," he said.

"We should not be spending too much time worrying about which of these two agents to use. Rather, the most important thing is that patients take one of them. But this is not happening in many patients. We have to work harder to get more patients treated," he stressed.

Underrecognized Risks?

Commenting on the findings for Medscape Medical News, David Spence, MD, professor of neurology and clinical pharmacology at Western University and director of the Stroke Prevention and Atherosclerosis Research Center, Robarts Research Institute, London, Ontario, Canada, said the results are what he would have expected.

As to which agent to choose, Spence points out that only clopidogrel is reimbursed for use in stroke in Ontario, but he believes the problems with clopidogrel are underrecognized.

"Approximately 30% of Europeans and more than half of Chinese people have the loss-of-function variant that results in reduced efficacy of clopidogrel. So, in my view, we should be using ticagrelor or prasugrel instead of clopidogrel," he said.

"I think dyspnea is a problem with ticagrelor, and there is recent evidence that in acute coronary syndrome, prasugrel was more efficacious, so if I had my choice, I would prescribe prasugrel," he added.

Spence believes bleeding complications could be markedly reduced by good medical care.

"Intracerebral hemorrhage is virtually eliminated by good blood pressure control, and probably many of the major gastrointestinal bleeds could be avoided by detecting and treating Helicobacter pylori. Antiplatelet agents and anticoagulants do not cause bleeding to start; they cause bleeding not to stop," he noted.

The THALES trial was funded by AstraZeneca. Johnston led the POINT trial of clopidogrel in stroke. He has received grants from AstraZeneca and Sanofi. Spence has disclosed no relevant financial relationships.

JAMA Neurol. Published online July 9, 2021. Full text

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