Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial
What are the reasons for the observed geographic variation in outcome associated with use of ticagrelor in the PLATO trial?
The authors performed a post-hoc analysis to assess the geographic variation in outcome in the PLATO trial, where the use of ticagrelor was associated with worse outcome in patients in the United States, whereas a significant benefit was observed among the rest of the patients. The analysis was conducted by two independent statistical teams. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy.
The analysis ruled out systematic error. Possibility of it being a chance finding could not be definitively excluded. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose ≥300 mg/d. A total of 37 baseline and postrandomization factors were explored, and only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, among patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort.
The result of this analysis suggests that the observed regional interaction in the PLATO trial could arise from chance alone or could be explained by an underlying statistical interaction with aspirin maintenance dose. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel was observed in patients on a low maintenance dose of concomitant aspirin.
This study defines the reasons for the geographic variation in outcome observed in the PLATO trial and suggests that the maintenance dose of aspirin may be a good explanation for this finding. While there is no good reason to use a higher maintenance dose of aspirin in patients on ticagrelor (or clopidogrel), one must be cautious about overinterpreting subgroup analysis (ISIS-2, Lancet 1988). I cannot imagine this variation would have received the same degree of scrutiny if this finding related to some other region of the world, or reflected a subgroup that did not have regulatory implications.
Keywords: Myocardial Infarction, Stroke, Platelet Aggregation Inhibitors, Ticlopidine, United States
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