Activity Transcript

John W.A. Eikelboom, MBBS, MSc: Hello, I'm John Eikelboom, professor of medicine at McMaster University, Hamilton, Ontario in Canada. Welcome to this program, entitled Factor Xa inhibitors in Coronary Artery Disease and Peripheral Artery Disease. Where Are We Today? Joining me today is Jeffrey Weitz, professor of medicine and biochemistry at McMaster University in Hamilton, Ontario, Canada. Welcome, Jeff.

Jeffrey I. Weitz, MD, FRCPC: Thank you, John. Happy to be here.

Dr Eikelboom: And also, Christoph Bode, professor of cardiology and angiology at the heart center Freiburg University in Freiburg, Germany. Welcome, Christoph, and welcome to our audience.

Christoph Bode, MD: Hello, John.

Dr Eikelboom: Well, we're going to take a short journey through the story of antithrombotic therapy in chronic atherosclerosis, and we're going to look at, why use antithrombotic therapy? What's the rationale for intensifying the therapy and then, we're going to talk about some of the more recent data that's informed this area, and how this has impacted the guidelines. And then finally, we'll come back and look at the application of these critically important advances to clinical practice.

Jeff, maybe I could start with you. Why are we using antithrombotic therapy in chronic atherosclerosis?

Dr Weitz: As you know, John, most of the acute complications of atherosclerosis are due to atherothrombosis, thrombosis superimposed on disrupted atherosclerotic plaque and plaque disruption activates two processes that occur simultaneously. The first is platelet adhesion activation aggregation and the second is activation of coagulation with thrombin generation. So, we use antithrombotic therapy to blunt the platelet response or to quiet down the thrombin generation. And we can attack it with antiplatelet agents alone, either used a singly or together in dual antiplatelet therapy (DAPT), or with anticoagulants or with a combination of both. And that's what we're going to be talking about today.

Dr Eikelboom: And Jeff and Christoph, to me it's striking that for many decades now, we've been trying to treat people with antithrombotics for cardiovascular prevention and the historical standard has been mainly antiplatelet therapy. Is it effective, and what else have we been using, and why should we be seeking better therapies now?

Dr Weitz: We have been focusing mainly on antiplatelet therapy for chronic secondary prevention, but we intensified therapy during acute events, such as during an acute myocardial infarction, for example. We intensify therapy using DAPT, and even short-term anticoagulation, but most of the focus, as you indicate, has been on the use of antiplatelet agents. If we use aspirin, we're only tackling one pathway of platelet activation. If we use DAPT therapy with aspirin plus a P2Y₁₂ inhibitor, then we're tackling two pathways of platelet activation. But even with DAPT, you can still get thrombin generation, and thrombin is the most potent platelet agonist. So, adding anticoagulant therapy makes sense. The problem in the past has been that it was very difficult to safely use anticoagulants together with antiplatelet therapy because of the bleeding complications.

Dr Eikelboom: Jeff, that's nicely described. I think in the acute phase, we've been more comfortable, because it's a short-term therapy, adding the anticoagulant with an antiplatelet drug, but Christoph, we've heard about the short-term period where we often combine an anticoagulant with antiplatelet therapy or indeed, we combine two antiplatelet drugs. But the big challenge is in long-term therapy. Can you tell us about where we've come from in long-term antithrombotic treatment?

Dr Bode: Not to go too far back in history, John, let me start with the Antithrombotic Trialists publication in the late 1990s. That is more than 20 years ago, and that is still the basis of all understanding of what aspirin does in secondary prevention of acute myocardial infarction. In that, they actually achieved with aspirin alone a 19% reduction of all-cause mortality. So, that is the basis. That is actually where we started from.

The CAPRIE study, a little later, how shown that clopidogrel alone can actually be a little bit more effective than aspirin, but it acted differentially on PAD, where it performed very well. It did not do as well in coronary artery disease. So, we are left with one study, a little bit of uncertainty. Early on, the combination of aspirin and clopidogrel provided actually better results, also long-term better results - and that is the CURE study, that the combination for at least a year after an acute event reduces deaths, and also that it is good to combine two antiplatelets over a longer period than one year. We do not at this point actually know for how long we should combine two antiplatelets in order to reduce cardiovascular events.

Dr Eikelboom: Christoph, that's a nice summary. And as of today, I think there are many people who still use single-agent antiplatelet therapy long term. There is promise with DAPT, but we are aware that when we carry on beyond one year, we can prevent non-fatal events. It does come at the cost of bleeding, but the holy grail of these treatments to further reduce mortality has really remained elusive, which brings us to the COMPASS trial, Jeff. COMPASS was published some time ago now, but here, the hypothesis was that adding a low dose of an anticoagulant to a single antiplatelet drug might be effective.

Dr Weitz: Right, John. That was the excitement here of what we call dual pathway inhibition. I said at the beginning that with atherothrombosis, there's activation of platelets and there's activation of coagulation, and those two processes are occurring simultaneously. So, the whole theory behind dual pathway inhibition is to tackle both of those arms of artherothrombosis. To give aspirin, to quiet down the platelets, and to give rivaroxaban in a low dose to attenuate thrombin generation, and to quiet down the coagulation pathway.

COMPASS, a trial that you led, was really unique, because one, it was a large trial. Two, is it took patients with CAD or PAD or both and randomized them to either that combination of aspirin plus low-dose rivaroxaban or to aspirin alone, and there was a third arm of rivaroxaban alone. What that study showed was about a 25% reduction in the rate of cardiovascular death, MI, and stroke with the combination of low-dose rivaroxaban plus aspirin compared with aspirin alone. That was a dramatic effect. And here, as you said, within the past for chronic therapy, we have been unable to show reductions in mortality, but yet there was a significant reduction in cardiovascular mortality with that dual pathway inhibition therapy.

Now, it comes at a cost of increased bleeding. It was about a 70% increase in major bleeding with the combination. However, there was no significant increase in intracranial hemorrhage or serious bleeding.

For the first time, we now have something to offer for our patients with CAD or PAD or the combination, polyvascular disease to further reduce their mortality, beyond that sort of 19% reduction that we saw with aspirin for secondary prevention way back about 20 years ago.

Dr Eikelboom: Jeff, one of the important findings, of course, of COMPASS is that these benefits were substantial in magnitude, and they're achieved on top of other proven secondary prevention therapies.

So, it comes as no surprise to me and Christoph, presumably, no surprise to you that guidelines around the world are going to change. Of course, the regulators have rapidly endorsed the use of the COMPASS dual pathway regimen. But what do we have so far about the impact on CAD guidelines?

Dr Bode: The European Society of Cardiology, and as European, I'm qualified to talk about them, say for chronic coronary syndrome, that the addition of a second antithrombotic drug to aspirin for long-term secondary prevention could be considered in patients with a high risk of ischemic events without a high bleeding risk. So, they actually opened the door, and they recommend the use of a second antithrombotic - that can actually be an antiplatelet or an anticoagulant. They are not definitive about which kind of agent it should be, but they say with a 2A recommendation that the second antithrombotic drug should added at a higher risk of ischemic events, rivaroxaban 2.5 mg twice a day, plus low-dose aspirin, the COMPASS regime, is among the endorsed regimens in the European guidelines.

Dr Eikelboom: Christoph, none of us are surprised by this endorsement of intensification of therapy, but it seems to me that Europe is ahead of the pack here, as some of the other guidelines are still to endorse this elsewhere. I think it's going to be inevitable. Jeff, what about PAD?

Dr Weitz: PAD, if we step back and look at what we had for those patients, we were either giving low-dose aspirin for secondary prevention or based, as Christoph said, on the data from the CAPRIE trial, many vascular specialists were giving clopidogrel, because it was slightly better than aspirin in the CAPRIE trial, particularly in the PAD patients. That's all we had.

But now, if we look at the PAD patients that were included in COMPASS, in these patients, they get two bangs for the buck, because they get about a 30% reduction in MACE, the composite of CV death, MI, and stroke, and they get an almost 50% reduction in major adverse limb events, which includes things like acute limb ischemia, major amputation. This is huge, because before, all we had with single antiplatelet therapy was a modest reduction in risk, and now we get not only a reduction in cardiovascular events, but also a reduction in adverse limb events.

I think that PAD patients, John, are the low-hanging fruit. Not that there aren't a lot of patients who could benefit from the COMPASS regimen, but those PAD patients can really benefit and they get the two arms, the generalized events, CV events and the reduction in adverse limb events.

Dr Eikelboom: That impressive result has been reflected in some of the recent PAD guidelines. When one looks back at the COMPASS trial, folks say, "Well, it was one trial." In fact, the breadth of the data is already enormous because remembering that the original dual pathway treatment evaluation, the ATLAS trial, which included more than 10,000 patients, showed a benefit of this regimen in the ACS patient. We now have COMPASS in the chronic coronary and peripheral artery disease population, and then, hot off the press, new data that further supports this.

Christoph, I'm going to ask you to comment first. We have the new COMPASS PCI data. So, this is a subanalysis of the COMPASS trial, and very impressive results. Can you remind us what this showed?

Dr Bode: In the very impressive results, as you say, let me remind you of the 27,000 plus patients in COMPASS, 16,560 of these CCS patients were randomized to either DPI or aspirin, 16,000 plus patients. 59.6% of these CCS patients have had a PCI in the past. The new finding in COMPASS PCI is now that, regardless of prior PCI, DPI vs aspirin alone produced consistent reduction in MACE, namely 4.0% vs 5.5% in patients with PCI, a reduction of 26%, or 4.4% vs 5.7% for patients without previous PCI, a reduction of 24%. And probably even more important than that, there is not only a reduction in MACE, but also a reduction in all-cause mortality. Like shown in the PIONEER trial, and this is for patients with PCI from 3.5% to 2.5%, a reduction of all-cause mortality 27%. And for those without PCI, from 5% to 4.1%, a reduction of 20%.

Dr Eikelboom: What's remarkable, Christoph, here is that the mortality reduction was evident, not just in people with a recent PCI, but right up to five to 10 year prior history of PCI. And I think that's going to be very reassuring to the interventional community.

Dr Bode: This is hot news to the interventional community. And I can tell you, it will also probably shift the compass a little bit toward DPI.

Dr Eikelboom: Jeff, we've not only seen advances in the post-PCI setting, but the other very hot news item is the VOYAGER trial. So, VOYAGER testing this same regimen in the revascularized PAD patient and the results? Can you remind us what this trial showed?

Dr Weitz: I can, John. This is exciting, because for the PAD population, you could wonder from COMPASS, when do you start dual pathway inhibition in the patient who has undergone revascularization surgery? And that was the question that was asked in the VOYAGER study. So, approximately 6500 patients with PAD undergoing revascularization procedures of the lower extremities, either endovascular or surgical, and they were randomized to the COMPASS regimen of rivaroxaban 2.5 mg twice daily plus aspirin or aspirin alone. And for this study, the primary efficacy outcome was a composite of both the limb and CV events. So, it was the composite of acute limb ischemia, major amputation for vascular causes, plus MI, ischemic stroke, and death from CV causes.

Over a three-year period, DPI reduced that composite efficacy outcome by about 15% that came at a cost of about a 40% increase in major bleeding, defined either using the TIMI scale or the ISTH criteria. So, there is some increase in bleeding, but again, you get this dramatic reduction in both limb and MACE events.

This takes us, in the PAD population, John, right back to the time of intervention for those patients who have the most severe PAD, or you back it up a bit from COMPASS, and you say, even in the patients who haven't got to that extreme that they need intervention, but they have, say, a claudication and they have evidence, perhaps of polyvascular disease, those patients, too, could benefit. I think what's fascinating here, John, is that we now have three trials. We have ATLAS, COMPASS, and VOYAGER all looking at this DPI strategy, and all have shown a benefit.

Dr Eikelboom: The beauty is that in both CAD and PAD, we now also have very good evidence that starting in the acute phase and continuing in the chronic phase can work with this dual pathway regimen. Almost 50,000 patients, a consistent, coherent, comprehensive set of data to inform practice. What I'd like to do now for a moment, just two or three minutes per case, provide some insights.

Christoph, I'm going to start with you. How do we now incorporate these data into clinical practice and why don't you give us an example in the CAD population, a patient who's had a previous MI.

Dr Bode: Well, typically, that patient with a MI comes to the cardiologist a year after the incidents, in order to scale down from DAPT to monotherapy. And we will have to ask the question now in the long run, will that patient probably profit from DPI more than from aspirin alone? Typically, the patient comes and sees me, at least here in Germany, is a patient that is around 70 years old, and many of our patients are diabetic. For many of these patients, are at a little bit of a higher risk.

According to guidelines, patients with a past MI would have that higher risk, that have an indication towards DPI. But many of these patients are even at a higher risk. They usually come and ask you, "Doctor, can we get rid of the pills?" And I'll have to tell them we can't get rid of all of the pills, but we have to retain some lifesaving medication. Now, we know that DPI saves lives reducing all-cause mortality in the patient of 18%.

Dr Eikelboom: So, it provides a really nice entry for the dual pathway therapy one year post-MI. Jeff, in PAD, how do you see the DPI impacting clinical practice?

Dr Weitz: In the PAD patient, we have now something more to offer them than just aspirin or clopidogrel. And with VOYAGER, we have a new entry point. Someone with PAD, who's undergone revascularization, that's the time to start DPI. For patients with intermittent claudication, has any CAD, that's low hanging fruit, those patients should be on DPI, and we hope that such therapy will prevent them from getting to the point where they need revascularization therapy.

I really think here, John, that we now have something for these patients. I'd like to see this widely embraced to really reduce the frequency that these patients come to the point where they get acute limb ischemia, or they get to the point where they have such severe claudication that they need revascularization therapy. But if they do get to that point, for sure, those patients should be considered for dual pathway inhibition.

Dr. Eikelboom: Well, Jeff and Christoph, it's been a great journey of the development of antithrombotic therapy, both in the acute vascular events and in the chronic phase. It's a good story, and it just keeps getting better. Unfortunately, we're running out of time, so we're going to have to draw this to a close.

Again, Jeff and Christoph, thank you so much for joining me in this discussion. Thank you to our audience for participating in this activity, and please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.