NEW YORK (Reuters Health) – In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor and clopidogrel were associated with similar rates of major bleeding, but ticagrelor was associated with increased rates of non-procedure-related bleeding.
Study investigator Dr. Richard C. Becker of Duke University School of Medicine, Duke Clinical Research Institute in Durham, North Carolina, told Reuters Health the “net clinical benefit” favored ticagrelor and “was preserved across a broad spectrum of patient subgroups.”
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.
The PLATO trial included 18,624 patients from 862 centers in 43 countries hospitalized for acute coronary syndrome (ACS), with or without ST-segment elevation, between 2006 and 2008.
A total of 9333 patients were assigned to treatment with ticagrelor, 180 mg as a loading dose followed by 90 mg twice daily, and 9291 were assigned to receive clopidogrel, 300-600 mg as a loading dose and then 75 mg per day. Follow-up continued to February 2009; the median duration of exposure to the study drug was 277 days.
The results – published in August 2009 in the New England Journal of Medicine and reported by Reuters Health at that time – suggested greater efficacy for ticagrelor in reducing the incidence of death from vascular causes, myocardial infarction, or stroke, without increasing the overall rate of major bleeding.
A new analysis from the PLATO trial, online November 16 in the European Heart Journal, “provides a comprehensive view of bleeding complications in patients with moderate-to-high risk ACS receiving contemporary platelet-directed therapy,” Dr. Becker told Reuters Health.
The safety population included 18,421 patients – 9,235 treated with ticagrelor and 9,186 treated with clopidogrel.
Rates of major bleeding were similar in the two groups using three different definitions: “PLATO” major bleeding (11.6% for ticagrelor vs 11.2% for clopidogrel), “TIMI” major bleeding (7.9% vs 7.7%) and “GUSTO” severe major bleeding (2.9% vs 3.1%).
Procedure-related bleeding rates were also similar with ticagrelor and clopidogrel, but non-CABG major bleeding (4.5% vs 3.8%) and non-procedure-related major bleeding (3.1% vs 2.3%) occurred more often with ticagrelor. Fatal events were uncommon and occurred at similar frequency between the two arms.
Despite the very low rate of intracranial bleeding in the PLATO trial, there were still a greater number of events in the ticagrelor than the clopidogrel treatment group. “This observation may reflect an inherently greater risk of intracranial bleeding with more intense platelet inhibition,” the authors say.
They point out that after adjusting for patient-related, clinical, and laboratory variables, including region, age, final diagnosis, history of transient ischemic attack or stroke, aspirin on the day of randomization, creatinine clearance, baseline hemoglobin, and Killip class, the net clinical benefit favored ticagrelor throughout the study, particularly after 30 days on treatment.
Commenting on these results, Dr. Becker said, “Clinicians caring for patients with ACS must always consider the risks and benefits of therapy, both in the acute and long-term setting. Ticagrelor has been shown to reduce the risk of vascular death, MI and stent thrombosis compared to clopidogrel without increasing the risk of fatal bleeding.”
AstraZeneca, sponsored the PLATO trial, participated in the design and oversight of the trial and coordinated data management.
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