AT THE INTERNATIONAL STROKE CONFERENCE
HOUSTON (FRONTLINE MEDICAL NEWS) – The combination of ticagrelor and aspirin reduced the incidence of high on-treatment platelet reactivity compared with clopidogrel plus aspirin in an interim analysis of a trial of patients with minor acute ischemic stroke or high-risk transient ischemic attack, but was associated with more treatment-limiting side effects.
Significantly more patients taking the ticagrelor combination dropped out because of dyspnea and minor bleeding, Yilong Wang, MD, said at the International Stroke Conference, sponsored by the American Heart Association. Although the ticagrelor combination also prevented a few more recurrent strokes than did clopidogrel plus aspirin, the difference was not statistically significant.
Dr. Wang of Beijing Tiantan Hospital reported the results as part of an interim safety and efficacy analysis of the Platelet Reactivity in Acute Stroke or Transient Ischemic Attack ( PRINCE ) trial.
The Chinese study is observing the potential benefit of ticagrelor in an Asian population in which a loss-of-function cytochrome CYP2C19 allele is somewhat common. This allele has recently been associated with a diminished response to clopidogrel in patients who need antiplatelet therapy after having experienced a minor stroke or high-risk transient ischemic attack ( JAMA. 2016;316:70-8 ).
“Ticagrelor has been shown to be more effective in acute coronary syndromes than clopidogrel, regardless of genotype, as it is primarily metabolized by the cytochrome P3A4 enzyme,” Dr. Wang said. “In the SOCRATES Asian substudy , we saw a trend of better efficacy in reducing the risk of subsequent vascular events in the ticagrelor group. But there are limited data on the safety and efficacy of ticagrelor, compared with clopidogrel, over background aspirin in stroke patients.”
PRINCE sought to determine the safety of ticagrelor plus aspirin and their effect on platelet reactivity and clinical outcomes in Asian patients who had experienced a minor stroke or high-risk transient ischemic attack (TIA). The 90-day trial is being conducted in 26 centers in China. Its primary endpoints are P2Y12 reaction units (PRU) and the number of patients with high on-treatment platelet reactivity. Secondary outcomes were the incidence of stroke at 90 days, and a composite vascular outcome of any stroke, heart attack, or vascular death within 90 days.
The primary safety outcomes were major and minor bleeding, intracerebral hemorrhage, and total mortality. The study’s researchers hope to enroll 952 patients. The interim analysis was conducted in 476 who have completed the treatment and follow-up period.
The ticagrelor group (237) received an initial loading dose of 180 mg with 100-300 mg aspirin on day 1, followed by 180 mg ticagrelor plus 100 mg aspirin for 21 days. Thereafter, they discontinued the aspirin and continued with 180 mg ticagrelor.
The clopidogrel group (239) received a 300-mg clopidogrel loading dose plus 100-300 mg aspirin on day 1, followed by 75 mg clopidogrel and 100 mg aspirin daily for 21 days. Thereafter they discontinued the aspirin and took 75 mg clopidogrel daily.
Patients were a median of 60 years old. Most (75%) were male. The median blood pressure was 152/90; 60% were hypertensive. About a quarter had diabetes. The qualifying stroke was a TIA in 22%; the rest had a minor ischemic stroke. The median National Institutes of Health Stroke Scale score was 2.
Platelet function was measured at baseline and 2 hours after the initial loading dose, and then again at 24 hours, and at 7, 21, and 90 days.
The baseline PRU was about 250 in each group. Two hours after the loading dose, it dropped significantly more among those taking ticagrelor than in those on clopidogrel (45.7 vs. 222.32). It remained significantly lower at every time point. At 90 days, the PRU favored ticagrelor (69 vs. 175).
Ticagrelor was also associated with significantly less high on-treatment platelet reactivity at every time point. The final separation at 90 days significantly favored ticagrelor (13% vs. 30%).
Clinical endpoints numerically favored ticagrelor, although none of the findings were statistically significant. Any stroke occurred in 4.6% of the ticagrelor group and 7.5% of the clopidogrel group. The rate of ischemic stroke was 4.2% and 6.7%, respectively.
There were three deaths: two in the ticagrelor and one in the clopidogrel group, and three major bleeds in each group. There was no significant difference in minor bleeding or intracerebral hemorrhage. However, ticagrelor was associated with significantly more incidents of minimal bleeding (17% vs. 7%). This difference drove the final, statistically significant doubling of bleeding risk associated with ticagrelor (hazard ratio, 2.26).
There were 49 adverse events leading to dropouts. Most of these were due to bleeding, which was significantly higher in those taking ticagrelor (12 vs. 5 events). Dyspnea was the next-leading cause of study dropout (5 vs. 1 case). The remainder of the dropouts were due to study noncompliance and patient decisions.
The study will continue, Dr. Wang noted.
PRINCE is being sponsored by the Chinese government. Dr. Wang had no financial disclosures. AstraZeneca is providing the study drug at no charge, and is not otherwise involved in the trial.
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