Abstract
The ONSET-OFFSET study was a multicentre study assessing the pharmacodynamic responses to ticagrelor and clopidogrel in aspirin-treated patients with chronic coronary syndromes. Recent concerns have been raised about the study methodology, including at the single United Kingdom (UK) site in Sheffield. Here, we report data generated at this site along with additional analyses. The UK site recruited 40 out of 123 of the study participants. Platelet P2Y(12) receptor inhibition was assessed using light transmission aggregometry and whole-blood methodologies. Samples were obtained during the onset and offset dosing periods. Percentage inhibition of platelet aggregation (%IPA) was calculated with (pre-specified) and without (post hoc) truncation of values [0, 100]. Study conduct was monitored by an external contract research organisation. The results from the UK site were concordant with the main study findings. %IPA at 2 h after ticagrelor loading: main study 88%, UK site 91% (truncated), UK site 91% (untruncated). %IPA correlated with other measures of P2Y(12) inhibition (VerifyNow: p < 0.0001; VASP phosphorylation assay: p < 0.0001). One patient treated with ticagrelor had >2 h delay in the onset of platelet inhibition associated with co-administration of metformin. The primary endpoint for the offset period was also similar to the main study findings. The UK site data confirm the more rapid onset and offset of inhibitory effects and greater mean levels of platelet inhibition with ticagrelor compared with clopidogrel, regardless of the mode of %IPA data analysis. Study conduct was rigorously monitored in order to demonstrate the integrity and validity of the results. Metformin may delay the onset of action of a ticagrelor loading dose.