The Future for NOACs in Light of ENGAGE-AF
Dr Ohman: At this meeting, there was also an overview analysis taking all the studies together. Can you summarize that for us? What's the take-home message for you when all of these trials were put together?
Dr Mega: Sure, this is really interesting. There are over 70 000 patients in this meta-analysis, and if we just pause for a minute and think about the number of subjects that were in the warfarin trials, the earliest type of trials, stroke prevention for atrial fibrillation, had a couple of thousand patients. Now we have a huge amount of data, and I think it is worthwhile to pause for a minute and say what an amazing accomplishment over the past few years. Looking at the data, what was seen in general—as we started to allude to at the beginning of the talk—is the overall efficacy profile is at least as good [as warfarin]. We have to remember these drugs were just created to be noninferior—that is, to be just as good as warfarin—and they're at least just as good. On the safety side from an ICH perspective, there is definitely a reduction. Some of the trials have shown a slight increase in GI bleeding, and in talking to hematologists whom I respect, the way they've described it to me is that there may be different reasons you bleed into your brain vs into your GI system. Then, on the mortality side, all these trials, when they're combined, show that there's a benefit. It is interesting, as we said, that the messages are similar. The question in two of the trials was a low dose vs a high dose. We know the low-dose strategy tends to be safer, but in terms of the ischemic benefit it may not be quite as good.
Dr Ohman: That's remarkable. So 70 000 patients with nonvalvular atrial fibrillation were examined, and we got a very consistent message. Where do you see the gaps? Where do we need to go next? Is it valvular disease, although there's been some trials regarding that with some challenges, but what basket would you put your eggs in next to move this forward?
Dr Mega: I think there are two areas that deserve further attention: one, the data thus far with valvular disease have not been as encouraging—is it something about a particular drug or a particular dose? With all of these agents, I've been so struck by the importance of dosing. With antithrombotic therapies, there really is a sweet spot. Think about warfarin; you're trying to get between an INR of 2 and 3. When you have too much antithrombotic therapy, it's not going to help; too little, you're in trouble. That's one area. The second one, which is starting to get some attention, is what are we doing with patients who have atrial fibrillation (or other indications for full-dose anticoagulation) but who also have acute coronary syndrome or the need for percutaneous coronary intervention, and so from the ATLAS programs the suggestion was that aspirin, clopidogrel, and very low-dose rivaroxaban, so, a fourth of the standard dose of rivaroxaban that was a beneficial regimen. On the other hand, what are we going to do with these patients where we would say, "Wow, this patient needs full anticoagulation"? There's some really exciting work being done in this area, so we'll need to follow that.
Dr Ohman: Very exciting, and what I'd like to emphasize is the fact that there's more work to come, because we've just started in an area of medicine that is really novel, that we have a lot more to learn from. I want to thank you, Jessica, for participating today.
Dr Mega: Thank you.
NOAC Meta-analysis
Dr Ohman: At this meeting, there was also an overview analysis taking all the studies together. Can you summarize that for us? What's the take-home message for you when all of these trials were put together?
Dr Mega: Sure, this is really interesting. There are over 70 000 patients in this meta-analysis, and if we just pause for a minute and think about the number of subjects that were in the warfarin trials, the earliest type of trials, stroke prevention for atrial fibrillation, had a couple of thousand patients. Now we have a huge amount of data, and I think it is worthwhile to pause for a minute and say what an amazing accomplishment over the past few years. Looking at the data, what was seen in general—as we started to allude to at the beginning of the talk—is the overall efficacy profile is at least as good [as warfarin]. We have to remember these drugs were just created to be noninferior—that is, to be just as good as warfarin—and they're at least just as good. On the safety side from an ICH perspective, there is definitely a reduction. Some of the trials have shown a slight increase in GI bleeding, and in talking to hematologists whom I respect, the way they've described it to me is that there may be different reasons you bleed into your brain vs into your GI system. Then, on the mortality side, all these trials, when they're combined, show that there's a benefit. It is interesting, as we said, that the messages are similar. The question in two of the trials was a low dose vs a high dose. We know the low-dose strategy tends to be safer, but in terms of the ischemic benefit it may not be quite as good.
Where To Next?
Dr Ohman: That's remarkable. So 70 000 patients with nonvalvular atrial fibrillation were examined, and we got a very consistent message. Where do you see the gaps? Where do we need to go next? Is it valvular disease, although there's been some trials regarding that with some challenges, but what basket would you put your eggs in next to move this forward?
Dr Mega: I think there are two areas that deserve further attention: one, the data thus far with valvular disease have not been as encouraging—is it something about a particular drug or a particular dose? With all of these agents, I've been so struck by the importance of dosing. With antithrombotic therapies, there really is a sweet spot. Think about warfarin; you're trying to get between an INR of 2 and 3. When you have too much antithrombotic therapy, it's not going to help; too little, you're in trouble. That's one area. The second one, which is starting to get some attention, is what are we doing with patients who have atrial fibrillation (or other indications for full-dose anticoagulation) but who also have acute coronary syndrome or the need for percutaneous coronary intervention, and so from the ATLAS programs the suggestion was that aspirin, clopidogrel, and very low-dose rivaroxaban, so, a fourth of the standard dose of rivaroxaban that was a beneficial regimen. On the other hand, what are we going to do with these patients where we would say, "Wow, this patient needs full anticoagulation"? There's some really exciting work being done in this area, so we'll need to follow that.
Dr Ohman: Very exciting, and what I'd like to emphasize is the fact that there's more work to come, because we've just started in an area of medicine that is really novel, that we have a lot more to learn from. I want to thank you, Jessica, for participating today.
Dr Mega: Thank you.
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