Patterns of Event Adjudication in the United States PLATO Trial Cohort

Author(s): Victor Serebruany, Hector A, Cabrera-Fuentes, Wendy Ziai, Efrén Emmanuel Jarquín González, Isabella Hwang, Wiktor Kuliszkowski, Dan Hanley

Objective: To compare patterns of central event adjudication in the United States (US) versus the Rest of the World (RW) within the indication-seeking Platelet Inhibition and Clinical Outcomes (PLATO) trial assessing the efficacy and safety of ticagrelor versus clopidogrel in patients with acute coronary syndrome.

Background: Adjudication in randomized, outcome-driven trials is intended to maintain integrity by applying uniform rules for the quality assessment of clinical events. However, despite the reported ticagrelor benefit in the RW the US PLATO outcomes were inverted lacking reasonable explanation.

Methods: We analyzed the FDA-issued PLATO adjudication dataset, focusing on potential treatment favoritism, the impact of disagreements, and prevailing diagnostic decisions in the US versus the RW.

Results: Among 18,624 (1,413 US) trial enrollees 10,705 (1,003 US) events occurred across 7,171 (973 US) patients. There were 938 deaths (53 US), 2,752 (242 US) MI's, 367 strokes (23 US), and 3,822 (368 US) bleedings. Matches occurred for 7,240 events (653 US), while mismatches favoring clopidogrel (n = 1,715) or ticagrelor (n = 1,708) (p = 0.195) were common across major (n = 1,789), moderate (n = 932), and minor (n = 727) disagreements. The central diagnostic decision prevailed in 2,945 cases (295 US). Significant adjudication favoring ticagrelor was observed for bleeding (HR = 1.17; CI: 1.01–1.35; p = 0.037), trends for vascular death (HR = 1.20; CI: 0.64–2.25), MI (HR = 1.31; CI: 0.96–1.78), and stroke (HR = 2.04; CI: 0.62–6.70) in the US. Adjudication disagreements for combined primary events heavily favored ticagrelor in the US compared to the RW (HR = 1.35; CI: 1.16–1.56; p = 0.03).

Conclusion: Ticagrelor favoring in the PLATO-US cohort adjudication suggests unblinding. Among all countries, the CRO - monitored PLATO-US site-reported, but not adjudicated outcomes, represent the largest and most reliable dataset of realistic verified evidence suggesting ticagrelor inferiority to clopidogrel.