BMJ Uncovers Gaps in Ticagrelor Trial Integrity

With generic versions of ticagrelor (Brilinta) entering the market, The BMJ is scrutinizing the drug’s original clinical trials, raising significant questions about the reliability of the evidence that has guided antiplatelet therapy for over a decade.

Building on concerns raised about the pivotal PLATO trial, The BMJ now highlights troubling irregularities in two key AstraZeneca-sponsored pharmacodynamic studies, ONSET/OFFSET and RESPOND, that were instrumental in promoting ticagrelor’s faster and superior platelet inhibition over clopidogrel. These phase 2 trials, widely cited and published in Circulation, are alleged to have overstated efficacy, with at least one study failing to meet its primary endpoint as originally defined.

The BMJ obtained datasets submitted to the FDA and correspondence from a platelet test device manufacturer. These documents revealed inconsistencies. At one site, platelet data appeared to be collected the day after a device was shipped, raising questions about how testing began so quickly. Another site performed over 200 tests before test cartridges were officially recorded as delivered. The investigator at that site stopped responding to inquiries after several emails.

In addition, some machines were returned for servicing with stored platelet activity data still intact. At lead investigator Paul Gurbel’s site, The BMJ found over 60 platelet readings missing from datasets submitted to the FDA, which is roughly one-quarter of the total, and these excluded values showed significantly higher platelet activity than what was published. Furthermore, no patient identifiers were linked to those measurements, making it impossible to trace their origin or inclusion in trial analyses.

The volume of required blood drawings was unusually high, up to 604 mL across visits, posing recruitment and retention challenges. Some investigators were reportedly misattributed as authors, while others denied participation altogether. Additional analysis revealed missing baseline tests, misapplied statistical adjustments, and an undeclared change in the primary endpoint that converted a non-significant result into a statistically significant one.

The BMJ‘s analysis uncovered over a dozen patients in the RESPOND trial with incredibly low baseline platelet aggregation levels (<50%), which is atypical for stable, non-hospitalized individuals. Some showed increased platelet aggregation after receiving ticagrelor, an effect contrary to expectations for an antiplatelet agent, indicating likely lab errors. These questionable data points were included in some analyses but were masked in the primary endpoint analysis through an unpublished data adjustment.

Dan Atar, editor-in-chief of Cardiology, emphasized that such adjustments must be disclosed to allow proper evaluation of their validity. Furthermore, The BMJ found that the original trial protocol showed non-significant primary results (P=0.157), yet the Circulation publication reported significant results (P=0.005) after an undeclared change in the primary endpoint, thus altering the trial’s central conclusion about ticagrelor’s efficacy in converting clopidogrel non-responders.

An adjunct faculty member at Johns Hopkins University Victor Serebruany, who is one of ticagrelor’s most outspoken critics, told The BMJ, “There are instances of extreme rebound and deep platelet inhibition with ticagrelor that can leave patients vulnerable to thrombosis or bleeding. Had physicians been aware of what truly occurred in these trials, they likely would never have adopted ticagrelor in practice.”