Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

Abstract

on behalf of the PLATO Investigators Background-In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (Pϭ0.045), with less effect of ticagrelor in North America than in the rest of the world. Methods and Results-Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. 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. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose Ն300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in 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. Conclusions-The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872. (Circulation. 2011;124:544-554.)

Ticagrelor Use in Acute Myocardial Infarction: Insights From the National Cardiovascular Data Registry

“…This was hypothesized to be the main reason for the impaired efficacy and higher bleeding rate noted in patients in North America compared with the rest of the world, and was confirmed using Cox proportional regression and landmark analyses after evaluating 36 potential factors that could account for the observed geographical variation. This work by Mahaffey et al formed the basis for the FDA black box warning on discharge aspirin dosing in patients receiving ticagrelor 3. Nevertheless, there is currently a paucity of data describing the real‐world practice patterns of discharge aspirin regimen in the United States, and our report represents one of the first and largest analyses on this topic.…”

“…A subanalysis from PLATO identified a significant treatment–geographic region interaction ( P =0.045) and reported a reduced efficacy of ticagrelor versus clopidogrel in North American patients 3. A comprehensive systematic analysis independently identified differences in aspirin dosing as the likely reason for the observed interaction 4.…”

“Real‐World” Comparison of Prasugrel With Ticagrelor in Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention in the United States

“…First, while propensity score adjustment has been reported to eliminate > 90% of the treatment bias in observational cohorts, observational studies are still subject to residual and unmeasured confounding bias 14. Second, although aspirin dose was not captured in this study, the data here may represent outcomes associated with use of high‐dose aspirin (≥300 mg day −1 ) as the PLATO study demonstrated reduced efficacy of ticagrelor with high‐dose aspirin 23, an interaction not seen with prasugrel in TRITON‐TIMI 38 24. Third, while implications of ticagrelor‐induced nonplatelet side effects (e.g., dyspnea, ventricular pauses) and of a twice‐daily dosing regimen on medication adherence and discontinuation are largely unknown, these factors may confer an increased risk for subsequent cardiac events, especially given the more rapid offset of the antiplatelet effect of ticagrelor.…”

World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI

“…28 No increased risk of overall or intracranial bleeding existed with ticagrelor therapy in those with a history of stroke or TIA. 30 Subsequent analysis of the trial, spurred by the finding of no benefit in the North American cohort of patients, revealed that the benefits of ticagrelor over clopidogrel for reduction in ischaemic events are observed only when the daily aspirin dose is ≤100 mg, 31 which is now reflected in a recommendation on package labelling. 32…”