We have known for many years now that patients having an acute coronary syndrome (ACS) do better if they are immediately treated with aspirin, and that they do even better if in addition to that single antiplatelet agent they are also treated with clopidogrel.
In 2009, the PLATO trial was published in the NEJM. It was a randomized trial in more than 18,000 people having an ACS, comparing the benefits of adding either clopidogrel or the newer agent ticagrelor to aspirin. Ticagrelor appeared to cause some increased serious bleeding, but overall it reduced a composite endpoint of vascular death, MI, and stroke (hazard ratio 0.84). AstraZeneca, the manufacturer of ticagrelor, has to have been pleased.
Many subgroups were examined in PLATO, and in a few of them there was a suggestion of differences in effects across the subgroups; that is the benefit seen with ticagrelor was not as great or non-existent in three subgroups: those who weighed less, those not taking statins at enrollment, and those living in North America.
It's common when a trial examines multiple subgroups to find spurious positive results due to chance alone, given the multiple statistical tests being performed. For this reason, there has to be a good reason to bother to pay attention to a subgroup, and overly trusting subgroup analyses is one of the most common errors in thinking about what a study has shown. Given this, and the positive result in PLATO, it would have been typical for the authors to make short shrift of the subgroup analysis and write the results off to chance.
However, one of those subgroups seemed to worry the investigators. They wrote in the discussion section:
The difference in results between patients enrolled in North America and those enrolled elsewhere raises the questions of whether geographic differences between populations of patients or practice patterns influenced the effects of the randomized treatments, although no apparent explanations have been found.
They were likely concerned because the point estimate of effect in North America was that clopidogrel was substantially superior to ticagrelor, the opposite result from that seen elsewhere. However, ticagrelor was apparently approved by the US FDA without concern that the benefits seen in the trial as a whole would not apply to patients in North America, and that might well have been where things were left.
Instead, apparently working closely with authors/investigators at Duke, AstraZeneca carried out an extensive investigation to figure out whether the subgroup effect was real and, if so, what might have caused it. The article detailing this investigation was published in Circulation in 2011.
If you consider the problem, it is unlikely that genetic differences between North American patients and European patients could explain the differences. That suggests that if the finding was not caused by chance it was either due to some way in which patients were managed differently in North America (most likely) or some way in which patients enrolled in North America were consistently different (less likely), such as being sicker or older. Once you start looking for such possibilities, though, you are faced with the high likelihood of even more spurious results caused by chance. All the exploratory analyses are now post-hoc subgroup analyses -- those that you had not thought of before the primary analysis -- and so highly susceptible to findings due to the play of chance.
As they began looking into the issues, the investigators first found that the real difference wasn't between North America and the rest of the world, but really between the US and the rest of the world, so they refocused on the results when patients in Canada were included with the rest of the world. Then they checked in with major study sites to see if the trial was conducted differently in different locations -- it wasn't. Additional checks found that US sites seemed to have gotten the correct study drugs.
They looked at the play of chance, and concluded that results like those seen in North America would have been expected 32% of the time, and results like those seen in the US would have been expected in at least one country 10% of the time, so chance was certainly a possible explanation. Still, because US practices can be so different from those in many other countries, the investigators must have remained concerned.
The investigators then looked into many baseline and management variables to see if they could explain results and started focusing on aspirin dose as their investigation unfolded. At the US sites, patients were typically treated with more than 300 mg of aspirin (likely 325 mg) daily, while in other locations patients typically received less than 100 mg daily. In statistical analyses, including aspirin dose appeared to explain 80-100% of the regional variation in outcomes.
Additional analyses that stratified by aspirin dose found a dose response effect that seemed similar across regions. Patients in the US who received low dose aspirin saw similar benefits with ticagrelor to patients in the rest of the world, while patients in the rest of the world who received higher dose aspirin saw similar benefits with clopidogrel to patients in the US; patients in the rest of the world who received 100 to 300 mg of aspirin had similar outcomes with either clopidogrel or ticagrelor:
Overall, though, patients receiving low dose aspirin plus ticagrelor had the best outcomes:
Still, this is a post-hoc subgroup analysis, and the results may have all been due to chance. The authors of the paper acknowledge this repeatedly while still suggesting that patients treated with ticagrelor only be given low dose aspirin. This seems like a completely appropriate conclusion. We can't know for sure whether aspirin or chance or some other difference in management in the US explains the results, and it is unlikely that another RCT will be conducted to answer the question, but the analysis from this paper really informs appropriate clinical decision making.
I am not routinely a fan of Pharma in general or of AstraZeneca in particular. One of my favorite posts from the old medical humor website Q Fever does a wonderful job poking fun at the way in which AstraZeneca promoted Nexium over omeprazole (Prilosec) once the latter drug went off patent. The trials used to claim superiority for Nexium are great examples of how Pharma can manipulate results by manipulating study design and interpretation.
But as far as I can tell, AstraZeneca deserves real credit for pursuing the subgroup analyses from the PLATO trial. I can't picture how they could have seen a marketing upside to this, since they had already found an overall benefit with ticagrelor. If the issue were never pursued, the regional variation in effect would likely have been ascribed to chance. Furthermore, it was possible that the in-depth investigation they participated in would have turned something up showing that ticagrelor was no better than clopidogrel or was even inferior.
Instead of resting on the positive result in PLATO, AstraZeneca seems to have moved forward on this and supported the authors/investigators from Duke who clearly also wanted to pursue the issue. In so doing, they found what is likely the right explanation for what really happened in the trial, which allows patients throughout the world who receive ticagrelor to be treated with the appropriate dose of aspirin to maximize the chances of a favorable outcome.
The study's authors and investigators deserve our thanks for pursuing this issue with hard work and logical thinking, but it seems likely that thanks are due to AstraZeneca and its employees as well.