Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes

Abstract

The design and main outcomes of the PLATO trial (www.clinicaltrials. gov; identifier, NCT00391872) have been published. 11,12 PLATO was an international, randomized, double-blind, double-dummy, event-driven trial in patients hospitalized for acute ST-segment–elevation ACS scheduled for a primary PCI strategy or non–ST-segment–elevation ACS managed invasively or medically. Patients were randomized to receive either ticagrelor or clopidogrel within 24 hours of the onset of cardiac ischemic symptoms and before PCI. Ticagrelor-treated patients received a 180-mg loading dose followed by a maintenance dose of 90 mg twice daily. Clopidogrel-treated patients who had not already received a loading dose of open-label clopidogrel or who had not been taking clopidogrel or ticlopidine for ≥5 days before ran-domization received a 300-mg loading dose, followed by 75 mg once daily. The remaining patients received 75 mg clopidogrel as their first dose. Patients undergoing PCI received an additional 90-mg dose of ticagrelor/placebo at procedures >24 hours after randomization and, at the discretion of the investigator, an additional 300 mg clopido-grel/placebo at any time relative to randomization. All patients were recommended to receive 75 to 100 mg/d acetylsalicylic acid unless intolerant. For patients not previously receiving acetylsalicylic acid, a loading dose of 325 mg was preferred (although a dose of 160–500 mg was allowed). After stent placement, an acetylsalicylic acid dose up to 325 mg daily was allowed for up to 6 months and a lower dose was used thereafter. Randomized treatment was scheduled to continue for 12 months, but patients left the study at their 6-or 9-month visit if the targeted number of 1780 primary end-point events had occurred by then. It was recommended that study drugs be withheld in patients undergoing coronary artery bypass graft, 5 days for clopidogrel study drug and 24 to 72 hours for ticagrelor study drug, while maintaining the study blind. In each country, the study was approved by an insti-tutional review committee, and all subjects gave informed consent. Patients and Outcomes Enrolment in PLATO lasted from October 2006 to July 2008. In 2007, after the start of the study but before enrollment completion and data-base lock, a protocol amendment added stent thrombosis as an end point because it emerged as a major clinical concern in all trials involv-ing stent implantation. The present analysis pertains to patients who underwent stent placement during the trial or with a previous PCI. Potential events of stent thrombosis were identified by investigators and by systematic review of all deaths, suspected myocardial infarc-tions, and suspected recurrent ischemic events by a central adjudication committee blinded to treatment assignment but without review of cor-onary angiograms. Stent thromboses were defined using the Academic Research Consortium (ARC) definitions 13 as definite, probable, and possible and were categorized as acute (ie, occurring <24 hours of stent placement), subacute (occurring 24 hours–30 days after stent-ing), or late (occurring >30 days after stent placement). All analyses relating stent thrombosis to time since PCI were restricted to patients who underwent PCI after randomization. Compliant patients were defined as those taking blinded study drug at least 80% of the time, as measured by the investigator, during the observation period. For patients with premature discontinuation or withdrawal (eg, because of death, treatment discontinuation, or stent thrombosis), the observa-tion period for compliance stopped at the time of the event. Because interruption of antiplatelet therapy is a strong correlate of stent throm-bosis, an additional analysis adjusted for compliance to ensure that the treatment effect was not biased by differential rates of compliance to both treatments. Because compliance is a postrandomization char-acteristic, this analysis is exploratory and descriptive.