British Medical Journal (The BMJ)Doubts Over Landmark Heart Drug Trial: Ticagrelor PLATO Study

A recent BMJ investigation raises significant questions about the PLATO trial, which led to ticagrelor’s FDA approval in 2011. The investigation, supported by freedom of information requests and primary trial records, identified concerns about data reporting, regional outcome variations, and endpoint adjudication in the landmark study that established ticagrelor’s superiority over clopidogrel in acute coronary syndrome.

Key Points:

• The PLATO trial showed a 16% relative risk reduction in the primary endpoint (death from vascular causes, myocardial infarction, or stroke) with ticagrelor compared to clopidogrel (9.8% vs 11.7% at 12 months)
• US trial sites showed contradictory results, with ticagrelor patients experiencing a 27% higher risk of the primary endpoint compared to clopidogrel
• Post-licensure studies have consistently failed to replicate PLATO’s positive results, showing similar efficacy to clopidogrel but increased bleeding and dyspnea
• FDA records reveal that adjudication committee decisions disproportionately favored ticagrelor, with all six disputed death classifications affecting the primary endpoint favoring ticagrelor
• In 2022, US federal spending on ticagrelor exceeded $750 million, representing about two-thirds of total P2Y12 inhibitor costs despite comprising less than 10% of prescriptions

“Every time one of those negative trials came out, the news magazines would quote one of the investigators—who had an intellectual [and] financial bias—discounting it. And I said, ‘Wait a second, let’s just add up the skeletons here.'”
– Eric Bates, Professor of Internal Medicine, University of Michigan

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