Paul Dobesh, PharmD, FCCP, BCPS, shares data from several studies looking at the use of DOACs in the obese population.
Jessica Kerr, PharmD, CDE: Paul, talk to us about some of the studies that have compared the use of rivaroxaban with warfarin in your atrial fibrillation patients who are also obese. Give us an overview of the trials and then summarize our conclusions of how we might put that into true clinical practice.
Paul Dobesh, PharmD, FCCP, BCPS: It’s a big question. There’s a lot of information that has been coming out lately. One of the reasons I said earlier that that’s taken from ISTH in 2016 is probably outdated. Let’s just talk about DOACs in general and atrial fibrillation. One of the things that’s really interesting is also just from a kinetic standpoint. What’s the concern? Do you have enough drug to cover the space?
With rivaroxaban they did a study and they gave everybody—these are healthy volunteers—and just split them by weight. They took patients who were 70 to 80 kg—that was normal—gave them a dose of rivaroxaban, and measured peak levels and looked at area. Your total drug exposure and anti—Xa activity. Then they took obese patients and looked at patients who were over 120 kg; the average is in the mid-130s. It’s not as though they all hovered right around just 120, so it gives us some spread there. The average was in the mid-130s, and what they found was pretty fascinating. They found that the, the Cmax of the drug, the peak concentration of the total drug exposure, and most important, the anti-Xa activity and the anticoagulant effect was not changed almost at all. The variance is less than 10%, which in most of these types of kinetic studies is considered not a meaningful difference. This is what the ISTH didn’t think would happen. Rivaroxaban has shown that when you give the same dose to 2—of a regular patient size and a heavier patient size, there is no drop-off in the ability to keep adequate drug concentrations and anticoagulant effect.
When you look at apixaban, they did the same exact study: 70 to 80 kg, give them the dose with the patients, over 120 kg. Once again, the average is in the mid-130s. Interestingly, they found about a 20% to 30% drop in the peak concentration and the total drug exposure. What is most concerning is that there was a drop of over one-third in the anti-Xa activity. It’s not the same with apixaban in these heavier patients. Dabigatran has also been looked at in this setting, and its findings were kind of in between the 2. There was more of a drop-off but not as much as we saw with apixaban. The question really is, what does that mean for patients? Is it OK to have a drop-off of one-third of your anticoagulant effect? I don’t know. Unfortunately, that answer has not been really shown much for apixaban yet. We will talk about some of that data. With rivaroxaban, they went back and they looked at a post hoc analysis of the ROCKET AF trial. The ROCKET AF trial was the big FDA-labeling study with rivaroxaban versus warfarin. When they looked at that, what they found, if you believe the ISTH statement, is that the efficacy of rivaroxaban would fail compared with warfarin in heavy patients. But it didn’t happen. Even the patients, when they split them by a body mass index of 35, the average still favored rivaroxaban. You have to remember, we’re talking about subgroups. By definition they’re underpowered. But never did the movement of efficacy switch to better with warfarin. Never happened, even in the heaviest patients.
They’ve also done a number of real-world studies. And the real-world studies with rivaroxaban are pretty impressive in their follow-up time. One study by Peterson was done, and they looked at about 7000 patients. What they found is that the efficacy between warfarin and rivaroxaban, in these patients, all had to have a body mass index over 40. They used claims data. They all had to have a body mass index over 40. In those patients, remember, ISTH would have you believe that rivaroxaban is not going to work in those patients.
Actually, the efficacy was numerically better with rivaroxaban. Clearly there is no signal at all that the efficacy is failing. Bleeding was also numerically smaller with rivaroxaban. Finally, Costa and Coleman out of the University of Connecticut published another very large analysis. They actually used electronic medical records. The problem with using claims data is that marking obesity in claims is not done very well. It’s not easy because it’s missed, people don’t mark it, things like that. Claims data have some limitations. Unless you’re dealing with the morbidly obese—who are more commonly picked up by claims—patients who have a body mass index over 30, it’s hard to find reliable data with claims data. They actually used electronic medical records, which then had heights and weights and could calculate the BMI at the time of starting the drug. Its methods are very solid. They showed a significant reduction in thrombotic events and actually better bleeding, or less bleeding with rivaroxaban versus warfarin, in these patients. The culmination of that information with rivaroxaban has actually led to—you should see that rivaroxaban has shown that the ISTH statement is unnecessary with that agent, that the drug concentrations stay the same. Just as you’d expect, you know what, if your drug concentrations stay the same, your efficacy is going to be maintained. Safety is good, but this is a discussion about efficacy. The follow-up with these, like in the Peterson trial, was 10 months. The follow-up in the trial from the people from Connecticut was over 2 years. That’s a lot of follow-up for patients in these real-world studies.
Jessica Kerr, PharmD, CDE: What about any other key points of when we’re looking at the obese atrial fibrillation patients? Dr Johnson, if you want to chime in with some of your experiences with those applications of the trials.
Matthew Johnson, MD: Paul’s done a great job with those trials. When we look at it from a clinical perspective, I think we really look at those initial large randomized trials for atrial fibrillation, for instance. We really try to adhere to what the patient characteristics were. But when we start breaking down and looking at these analyses after the fact, and we have the VTE data that came out looking at obesity—as Paul alluded to, these guidelines are from 2016, and things are changing—I have to anticipate that some new guidelines may be coming out soon. They might call out that maybe 1 agent has a little more data in this realm than the others.