NOACs in the Anticoagulation Space - Episode 9

Effect of Comorbidities on the use of NOACs

March 4, 2020

Manesh Patel, MD: We’ve talked a lot about important aspects around AFib [atrial fibrillation] and the NOACs [novel oral anticoagulants]. What’s really interesting over the last few years is there have been other data and other information that has really helped us. Maybe we spend a little bit of time talking about how the field has moved past at least those initial studies. Let me—in maybe a little rapid fire—go through some comorbidities and ask you all how you think about these patients.

An AFib patient with coronary disease? New information about how we’re supposed to treat them. Maybe whether we could be giving them aspirin or not. How you think about them. Chris, you tell us a little about the information there.

Christopher Granger, MD: We have new information, and it’s incredibly important actually, and the new information that builds on prior information is that when you add aspirin to another anti-thrombotic, it’s highly predictable that you’ll get between a 50% and doubling risk of bleeding, including serious bleeding.

Manesh Patel, MD: And this is the AFIRE trial?

Christopher Granger, MD: Well, this is lots of trials now, but 1 of them. Actually, the combination of the AFIRE and the AUGUSTUS trials is really interesting too. This gets into issues of AFib and recent stents, or acute coronary syndromes [ACSs]. But there the AUGUSTUS trial is fascinating—4,600 patients factorial design.

We have aspirin versus placebo in 4,600 patients who are on an anti-coagulant and clopidogrel basically. There was a doubling in bleeding, including an increased risk of intracranial hemorrhage when you added aspirin. There was also some benefit right after stents, especially for the first 30 days. It looks like you prevent stent thrombosis.

Nonetheless, it nailed down in a high-quality way, again, that aspirin when added to it, to an anti-coagulant, doubles the risk of bleeding. The AFIRE trial is a trial run in Japan with rivaroxaban, 15 mg dose, which is what’s routinely used in Japan for atrial fibrillation stroke prevention. This is interesting—2200 patients who had stable coronary disease, most of them had had a stent at least a year before...

Manesh Patel, MD: Unlike AUGUSTUS, these patients had chronic coronary.

Christopher Granger, MD: Chronic stable coronary disease. They were randomized to an anti-platelet agent, usually aspirin, or no anti-platelet agent on top of their rivaroxaban. There was about a doubling in risk of major bleeding, no benefit in terms of additional antithrombotic effects, and a significantly higher risk of death. Small trial, not powered for the individual outcomes, but it really reinforced the idea that generally don’t use aspirin even in a patient with stable coronary disease who has AFib on an anti-coagulant.

Bernard J. Gersh, MBChb, DPhil, MACC: We all agree that over the last 5 years, in terms of aspirin, less is more. There are situations where you may still use aspirin, but aspirin is going away as an anti-thrombotic.

Manesh Patel, MD: That’s very fair. And maybe I’ll move us now from AFib.

Bernard J. Gersh, MBChb, DPhil, MACC: I don’t know if you’ve ever seen the study from England on aspirin and hangovers. It didn’t work. Their conclusion was that the best way to avoid a hangover is abstinence or moderation. I would add it wasn’t a study. It was just an article, a very funny article, in the December 24, 2005, issue of BMJ.

Manesh Patel, MD: Of course. Sean, if we move away from AFib and think about vascular disease, you know that’s a place where anti-platelet therapy had strongly been used for a long time. Now data from COMPASS have at least changed the way I think about low-dose rivaroxaban as a NOAC in that population. What was your response to that?

Sean D. Pokorney, MD: Especially in the PAD [peripheral artery disease] population, I think the data were very strong from COMPASS to prevent limb ischemia, and that was really a critical component of that trial. And I think the PAD population is a population we haven’t had a lot of great therapy for, and so in that population particularly I think that the low-dose anti-coagulation is valuable therapy.

Manesh Patel, MD: It was an interesting study. Actually, when they started I wasn’t sure. I remember when they said, “Oh, we’re going to do the COMPASS trial”—28,000 patients with coronary disease plus high-risk factors—“and we are going to use low-dose 2.5 mg twice a day of rivaroxaban plus aspirin compared with aspirin.” That’s a tall order, right, to look at cardiovascular events. A pretty powerful finding in that at least it was stopped early for a benefit for the 2.5 mg plus aspirin. It looks like, as you said, for patients with vascular disease, poly-vascular disease, coronary disease, and PAD or carotid disease, there was actually a pretty dramatic stroke reduction. Chris, how do you put that into practice? Is that hitting practice? Tell me how you think of it.

Christopher Granger, MD: It’s not really, right? It’s a single trial with a very compelling—it reduced mortality and reduced amputations. Manesh, you’ve been working for years in peripheral arterial disease to come up with something that reduces limb, ischemia, need for urgent revascularization or amputation. Now we have something that at least in 1 trial showed a pretty compelling result. As you pointed also, carotid disease has also this dramatic benefit.

But we didn’t see it in NAVIGATE ESUS, and we didn’t see it in COMMANDER HF. So it wasn’t reinforced by additional trials. The key is going to be VOYAGER, which I know you’re involved with, which will be reported out in the next several weeks.

Manesh Patel, MD: Yeah, maybe I’ll just give everybody a brief…

Bernard J. Gersh, MBChb, DPhil, MACC: Before that, can you comment on your own experience. You’ve shown that a more powerful anti-platelet agent was not more affective in the EUCLID trial.

Manesh Patel, MD: One thing we’re going to move away from as we go through this practice is that you know, for a long time we’ve been very coronary focused where a lot of patients are getting stents. When you put metal in people’s coronary stents, we’ve known for a long time clopidogrel plus aspirin, now this is from the PCI [percutaneous coronary intervention] subgroup of cure, but that was beneficial in ACS.

I’ll remind people that clopidogrel doesn’t have an indication for stents in an elective setting. It’s only in the ACS setting. But we’ve used them as interventionalists because we had to have something to use for our patients. When we did EUCLID we took 14,000 patients with PAD and we said a stronger anti-platelet agent, ticagrelor, would be beneficial compared with clopidogrel for coronary events and peripheral events.

In that peripheral population only 30% had known coronary disease. I’ve been saying that I think there’s a phenotypic difference with older PAD patients who got lots of atherosclerosis in their limbs and are having symptoms but have never had a coronary event. They may have atherosclerosis, but they’ve lived past when they might have it. At least in EUCLID we didn’t see a benefit, a stronger anti-platelet agent.

VOYAGER, to your point, and COMPASS speak to the idea that in addition to an anti-platelet therapy, if you could have another pathway that was affecting thrombin generation, either through factor Xa or as rivaroxaban does that, eventually that might help.

The COMPASS findings are powerful, but you’re right, we await VOYAGER. Just to remind the group, that’s a 6500-patient randomized trial taking patients after peripheral vascular intervention. They had a successful peripheral vascular intervention and a vascular or surgical—about a third of the patients had surgical revascularization. They got randomized to aspirin or aspirin plus rivaroxaban 2.5 mg twice a day.

Clopidogrel use was asked by the procedural at the start, and we stratified by the utilization of that. We’re going to know. It was randomized therapy, but we’re going to know if they wanted to use clopidogrel and they used it, how did that affect the treatment if there was any treatment?

Bernard J. Gersh, MBChb, DPhil, MACC: Would that include clopidogrel and aspirin?

Manesh Patel, MD: I’ll call it “1 arm,” so if you were doing endovascular and you said you’re going to use clopidogrel, then they got aspirin and clopidogrel and then rivaroxaban or placebo. I think it’s going to be powerful. At ACC [American College of Cardiology Scientific Sessions], there will be both the primary VOYAGER results and the clopidogrel analysis. We’ll be able to see that effect and hopefully answer both. I think that’s been important.

Transcript edited for clarity.