CardioExchange Archive

PLATO is one of the most impressive trials in recent years, demonstrating substantial benefits for ticagrelor over clopidogrel in a wide population of ACS patients. However, patients enrolled in the US showed no benefit from ticagrelor, and experts have been unable to agree on a cause. Possible factors could include much higher doses of aspirin used in the US versus the rest of the world, differences in baseline characteristics (the US population was heavier and had more diabetes), and different patterns of invasive procedures. It is also impossible to exclude the play of chance. At the recent FDA advisory panel which recommended US approval of ticagrelor, one FDA official summed up the dilemma: “this drug doesn’t do what it’s supposed to do in the country in which it’s being asked to get approved.”

CardioExchange asked several panel members and other experts to respond to 3 questions about the panel. Today’s installment is from panel member Jonathan Halperin, who voted in favor of approval. Our series started with the chairman of the ticagrelor panel, Sanjay Kaul, and continued with Mori Krantz, the one panel member who voted against approval. Tomorrow’s installment will be from Robert Harrington, who presented PLATO data to the panel on behalf of the sponsor.

1. What is your interpretation of the finding in the subgroup of US patients?

The finding in the patients enrolled in the US is subject to the usual limitations of subgroup analysis, particularly one that was not statistically adjusted for multiple comparisons, but may reflect regional differences in practice patterns that are incompletely explained by aspirin dose, length of hospital stay, and variations in criteria for various therapeutic interventions. Covariates that clearly correlate with differential outcome when tested in the international cohort, such as higher aspirin dose, should be addressed in future studies and, pending such additional data, should be considered by clinicians in decisions about how and when to employ ticagrelor in patient management.

2. How should this result influence the guidelines?

The apparently disparate findings should be addressed in the text accompanying guideline recommendations, but they carry insufficient weight in evidence to warrant recommendations that directly contradict conclusions derived from the primary outcome of the trial. The caveats mentioned in response to the previous query should be considered in the development of specific recommendations, and the limitations of a single study of any scope, including the possibility of systematic bias affecting the overall results, should be kept in mind when interpreting the results of PLATO, requiring confirmatory evidence in an independent trial cohort before these data can be considered as reflecting the highest level of medical evidence.

3. If approved now, whom would you treat with this drug… in the United States? and why?

My response would depend on the totality of evidence available, including information in the approved labeling, and economic considerations based on both the pricing of ticagrelor in the marketplace and, eventually, the comparative cost of generic clopidogrel, but available information would make me favor use of ticagrelor in situations when therapy is initiated early in the course of evaluation of a patient with a suspected acute coronary syndrome, to use a low dose of aspirin concurrently, and to terminate therapy earlier in patients with an eventual diagnosis of unstable angina pectoris without infarction than in those in whom myocardial necrosis is confirmed.