Ticagrelor-Aspirin Combo Beneficial After Minor Stroke

Nancy A. Melville

March 09, 2018

HOUSTON, Texas — A combination of the antiplatelet drug ticagrelor and aspirin shows some benefits over clopidogrel plus aspirin in the reduction of high on-treatment platelet reactivity among Asian patients with minor stroke or transient ischemic attack (TIA), according to the interim results of a randomized trial.

"Our study is the first trial to focus on the Asian population and verified that short-period use of ticagrelor plus aspirin was safe and feasible," first author, Yilong Wang, MD, PhD, from Capital Medical University and Beijing Tiantan Hospital, in Beijing, China, told Medscape Medical News.

With the risk for recurrent stroke increased following a minor stroke or TIA, antiplatelet therapy is recommended for prevention. Previous research, including the CHANCE trial, published in 2013 in the New England Journal of Medicine, has shown that clopidogrel combined with aspirin is more effective than aspirin alone in reducing the risk for recurrent stroke.

A genetic substudy, however, showed the benefits of the clopidogrel combination therapy over aspirin alone did not apply to patients carrying cytochrome CYP2C19*2 or *3 variants, which are more common in the Asian population.

Ticagrelor has meanwhile shown greater efficacy in acute coronary syndromes compared with clopidogrel, regardless of CYP2C19 positivity, in the PLATO trial, and was shown in a subgroup analysis of Asians in the SOCRATES study, published in January in Stroke, to be safe in Asian patients with stroke and TIA.

With data comparing the drug combinations in patients with minor stroke lacking, Dr Wang and his colleagues conducted the multicenter Platelet Reactivity in Acute Stroke or Transient Ischemic Attack (PRINCE) trial.

For the open-label trial, patients aged 40 to 80 years who had minor stroke or TIA were randomly assigned within 24 hours of the stroke to ticagrelor or to clopidogrel plus aspirin. The main outcome measure was the proportion of patients with high on-treatment platelet reactivity at 90 days.

Results from the interim analysis were presented here at the International Stroke Conference (ISC) 2017.

The results, representing findings on 476 of a planned total of 952 participants, showed that from the time of randomization to the 90-day cutoff, rates of stroke were not significantly different between the two groups: Eleven of 237 patients (4.6%) in the ticagrelor group had a stroke compared with 18 of 239 in the clopidogrel group (P = .18). Of those patients, 10 in the ticagrelor group (4.2%) had an ischemic stroke vs 16 (6.7%) in the clopidogrel group (P = .61).

In terms of the primary outcome of the proportion of patients with high on-treatment platelet reactivity at 90 days, defined as levels of P2Y12 reaction unit levels above 208, the mean rates were significantly lower in the ticagrelor plus aspirin group at 90 days (13.74%) than in the clopidogrel group (30.60%; P = .001).

"As expected, compared with clopidogrel plus aspirin, ticagrelor plus aspirin further reduced the proportion of minor stroke or TIA patients with high on-treatment platelet reactivity at 90 days," Dr Wang said.

Consistent with previous findings, the clopidogrel group had fewer bleeding events of any severity compared with the ticagrelor group (24 vs 50 events; P = .001), as well as fewer events of minimal bleeding (16 vs 40 events; P = .0007). However, major bleeding events were similar in both groups (3 events in each group; P = .96).

In the ticagrelor group, 35 patients discontinued the study drug because of adverse events, compared with 14 in the clopidogrel group. Twelve (5.1%) in the ticagrelor group discontinued because of any bleeding compared with 5 (2.1%) in the clopidogrel group, and 5 (2.1%) in the ticagrelor group discontinued because of dyspnea compared with 1 (0.4%) in the clopidogrel group.

Dr Wang noted that several factors may explain the higher dropout rates in the ticagrelor group.

"This might be associated with that Asian population are more sensitive to ticagrelor treatment than European patients," he explained. "Also, the higher dropout rate due to bleeding might be related to the fact that our trial was open label."

He added that a large-scale trial is necessary to determine the net benefit of reducing the risk for stroke recurrence after factoring in the increased bleeding risk.

Although the study did not look at effects specifically among carriers of the CYP2C19*2 or *3 variant, Dr Wang said the study's final analysis will include results of a subgroup analysis of those patients.

"We [expected] that there would be a greater difference between the two groups among people in that subgroup, but it will not be solid until the results finally come out," he said.

In the previous subanalysis of Asians in the SOCRATES trial, Dr Wang and colleagues reported that ticagrelor in Asian patients with TIA and acute (as opposed to minor) stroke was associated with a trend toward a reduced risk for stroke, myocardial infarction, or death in the ticagrelor group compared with those receiving aspirin alone.

The new study could build on those findings with added insights on the potential benefits of ticagrelor and aspirin, Demetrios Moris, MD, from the Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio, told Medscape Medical News.

"This trial answers indeed a very important question about the role of ticagrelor in the therapeutic armamentarium in patients with TIA/minor stroke," he said.

"Studying platelet reactivity with P2Y12 is an important contribution, but we already know that individual platelet response to antiplatelet therapy depends on a variety of factors."

Those factors include genetic background, cellular interactions, clinical factors (such as age, diabetes, smoking, and body mass index), and geographic origin, he noted.

"We assume that the authors will have adequately randomized the patients according to these characteristics."

The results in the final analysis of genetic distinctions will also be especially important, Dr Moris said.

"A comparison among carriers of 1 reduced-function allele (CYP2C19*1/*2, heterozygotes) and noncarriers (CYP2C19*1/*1, wild-type homozygotes) would be of great clinical importance, since studies on acute coronary disease have shown that the carriers of at least one CYP2C19*2 loss-of-function allele had marginally higher platelet reactivity and cardiovascular events when compared with noncarriers," he said.

"Additionally, the aspirin resistance rates in their population would be of paramount importance for better understanding of the results of the trial."

The study received funding from the National Natural Science Foundation of China, the Beijing Institute for Brain Disorders, the Beijing Municipal Science, and Technology Commission of Cerebral Vascular Disease. AstraZeneca provided the study drugs. The authors and Dr Moris have disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2017. Abstract LB12. Presented February 23, 2017.

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