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 were found to have 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. Our series started yesterday with the chairman of the ticagrelor panel, Sanjay Kaul, and continues today with Mori Krantz, the one panel member who voted against ticagrelor approval. Tomorrow we’ll have responses from another panel member, Jonathan Halperin. A subsequent 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?

PLATO is one of only a few trials demonstrating a mortality benefit versus active comparator, so its overall results can’t be discounted. In this context, the surprising findings in the US could reflect a statistical anomaly. However, a confluence of factors not definitively identified in the trial may have impacted the results. What’s ultimately problematic for me is that the US constituted nearly 1500 patients and 150 adjudicated events and was the sole signal of harm among 31 pre-specified subgroups.

Although variation in aspirin dose is a plausible explanation, post-hoc and non-randomized assessments must be viewed with skepticism. Beyond population differences (obesity, diabetes) there were also key care-process inconsistencies, including lower adherence, more coated stents, and a 50% shorter length of stay, which could account for the divergent results in the US.

2. How should this result influence the guidelines?

The current trial creates challenges for ACS management, since most of my patients receive coronary stents. The ACC/AHA guidelines recommend 162-325 mg/day of aspirin, and as seen in PLATO, most US clinicians prescribe 325 mg/day for a minimum of 1 month after bare-metal and 6 months after coated stent implantation. A guideline or labeling requirement for variable aspirin dosage depending upon which ADP-receptor antagonist is selected could be entertained, but would certainly complicate management. It begs the question, should therapeutic decisions be based on post-hoc exploratory analyses?

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

Despite the theoretic advantage of ticagrelor as a reversible platelet antagonist, there was no reduction in CABG–related bleeding. Given uncertainty around ticagrelor’s efficacy in the US and its BID dosing schedule (which resulted in lower adherence in US patients), it’s hard to identify a population I’m confident would derive incremental benefit over clopidogrel. I believe a confirmatory US trial would be essential for ticagrelor to become an accepted treatment of choice in ACS. Although, I was the only “no” vote among advisory panelists, I would point out that others suggested a US ACS trial was needed, but felt comfortable if it were performed post-approval.