August 6th, 2010

Three Questions about Ticagrelor: Part 4 — Bob Harrington

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. The fourth and final installment is from Bob Harrington, who presented PLATO data to the panel on behalf of the sponsor. Previous installments were with panel chairman Sanjay Kaul and panel members Mori Krantz and Jonathan Halperin.

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

Both the investigators and the sponsor have spent much time and effort thinking about the US subgroup effect. As was explained in some detail at the FDA meeting, we first explored any systematic issue such as a reversal of treatment codes or drug kits that might explain the effect. We could not identify any such issue. In fact, US ticagrelor patients have drug levels consistent with having received the drug, and a platelet function substudy conducted in US and UK sites show similar levels of platelet inhibition with ticagrelor. We next devoted substantial analytical effort to trying to understand if we could identify patient characteristics or patient care patterns that differed in US and non-US patients. There are some patient characteristics that do vary (weight and diabetes for example), but the differences do not explain the treatment effect differences. We looked at differences in concomitant medication use as well as procedural use, and after approaching the question from different analytical perspectives, the one consistent finding was that there was an association between maintenance aspirin dose and the observed treatment effect. Patients in the US are frequently (60% or so of the time) treated with aspirin at doses 300 mg, while use of these higher aspirin doses is far less frequent outside of the US (10%). After much analysis and thinking about the data, we believe that the use of higher aspirin doses in the US might be a plausible explanation for the observation. It’s not definitive. Only a randomized clinical trial could answer the question in a more definitive way, but it is a reasonable explanation. Of course, aspirin might be associated with some unknown factor for which we didn’t collect the data and therefore for which we can’t adjust in the analyses. Finally, the play of chance is possible here, though it seems less likely given the extreme nature of the US treatment observation.

2. How should this result influence the guidelines?

There are a lot of steps to consider here. First, the drug has to be approved in the US for the guideline writers to consider evaluating evidence and making recommendations. Second, the typical guideline process is to consider the peerreviewed literature as the key elements in understanding new therapies. Several papers from PLATO are now in the public domain. More will follow, including one devoted to these issues of aspirin and the US PLATO observations.

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

If the drug were available now, I would consider using it in patients presenting with an acute coronary syndrome defined along the entry criteria of PLATO. In PLATO, the overall effect and specifically the CV mortality effect favoring ticagrelor over clopidogrel are quite compelling.

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