Factor Xa Inhibitors: Clinical Trial Results in Atherosclerosis

Deepak L. Bhatt, MD, MPH: Along those lines, let’s switch gears a little bit to talk about anticoagulation: not in the setting of AFib [atrial fibrillation] where it’s generally full dose, maybe renally adjusted if it’s one of the NOACs [novel oral anticoagulants], but in the case of ACS [acute coronary syndrome]. If you could briefly review the APPRAISE-2 trial and the ATLAS ACS 2 trial, which used anticoagulants, which tested them in acute coronary syndromes largely on top of dual antiplatelet therapy [DAPT], a little bit of aspirin monotherapy, as well as background therapy.

John Eikelboom, MBBS, MSc, FRCPC: Deepak, when we think about an acute coronary syndrome, we know that at the time of that acute plaque rupture we get intense platelet activation, hence DAPT as a foundation, and out to, as we’ve discussed, a year. But we also get intense thrombin generation, so early on adding an anticoagulant with heparin or low-molecular weight heparin, or fondaparinux, has been the standard. We’ve tried to extend beyond that very early phase using one of the NOACs, and there have been a series of studies now. There’s a small one with dabigatran, a large one with apixaban, and an even larger one with rivaroxaban.

And what we’ve learned from these studies is that clearly, there is a benefit of adding an anticoagulant to antiplatelet therapy. But it’s all about hitting the sweet spot. And I think dabigatran was only a phase 2 trial, the RE-DEEM trial. The results are inconclusive because it’s too small. Apixaban was tested here at the standard AF [atrial fibrillation] dose, and the trial was stopped early because of an excess of bleeding. You could argue whether they should have pushed on because there was a hint of benefit. But I suspect that the dose was a little too high.

Deepak L. Bhatt, MD, MPH: There was some pretty bad bleeding too. It would have been hard to forge ahead.

John Eikelboom, MBBS, MSc, FRCPC: And the ATLAS ACS 2 trial I think hit close to the sweet spot: rivaroxaban 2.5 mg twice a day or 5 mg twice a day on top of aspirin, and we’re starting to see reductions in ischemic events. There’s a penalty to pay in terms of bleeding, but it translates into survival benefit. To me that’s the evidence that tackling coagulation, even in this early acute phase, is beneficial.

Deepak L. Bhatt, MD, MPH: And to be clear in that trial, it was really the rivaroxaban 2.5 mg bid [twice a day] that was reducing the risk of cardiovascular and all-cause mortality. It ended up not displacing patterns of care in the United States or really even elsewhere where DAPT remained the anchor despite that positive trial. But it did serve as an impetus to the COMPASS trial, which of course you were one of the principal investigators of. Can you tell us about that trial in broad terms, the inclusion/exclusion criteria?

John Eikelboom, MBBS, MSc, FRCPC: Certainly. COMPASS was, as you suggest, built directly on the ATLAS program, building on that success, the same doses of rivaroxaban tested in a slightly different manner. But here in chronic coronary artery disease [CAD] or peripheral artery disease [PAD]. The difference was that we obviously didn’t take the acute patient and we didn’t allow dual antiplatelet therapy. We went with rivaroxaban 2.5 mg twice daily in combination with aspirin, or rivaroxaban 5 mg twice daily alone, and the control was aspirin alone. You were leading the study in the United States and in the United States, the data show that most of these people are treated with aspirin alone, so that was the appropriate control group.

Deepak L. Bhatt, MD, MPH: Yes, that was the basic design of the study, a large study with 27,000 people in total. What were the findings?

John Eikelboom, MBBS, MSc, FRCPC: The findings were actually very straightforward, very clear-cut, and the trial was stopped early because that combination of therapy—rivaroxaban plus aspirin—compared with aspirin alone prevented major adverse cardiovascular events by about one quarter, reduced them by about a quarter. That was accompanied by about a one-fifth reduction in mortality. So when you see a reduction in cardiovascular events, you hope that will translate into survival benefits because if you’re preventing bad strokes and bad MIs [myocardial infarctions], you want to live longer. And there was a penalty to pay in terms of bleeding, but because I think the dose was close to the sweet spot, there was no increase significantly in fatal bleeding. And so you get a very clear net benefit.

Vamsi Krishna, MD: Speaking about PAD and antithrombotics and that sort of thing, is there anything you want to tell our audience about the VOYAGER PAD trial? Even in primary care, at least we need to be aware that it’s coming and what the implications might be.

Manesh Patel, MD: Yes. The VOYAGER PAD trial is a 6500 patient trial where we’re building on what was learned with COMPASS, which is to say, “OK, we now know chronically, taking patients who have atherosclerosis and thrombosis with CAD, PAD, and this variety of risk factors, this 2.5 mg dose with aspirin twice a day really seems to be potentially beneficial.”

Surprisingly without knowing that result but thinking that dose, because of ATLAS ACS 2, was going to be a good one, we had started a trial to better understand after revascularization. Because one of the other things is, we do want to inform the people doing the endovascular procedures or the surgical procedures. We’ve talked about endovascular, but the vascular surgeons take care of these patients who have equally high risk, and certainly these bypass graft surgeries—whether they’re veins or other conduits—have a thrombotic nature that leads again to limb harm.

And so we randomized 6500 patients, either they were getting an endovascular surgical procedure to a baseline of aspirin by itself, or aspirin plus rivaroxaban after the procedure. Now those patients were allowed to get clopidogrel for some duration if it was felt needed; we’ll stratify by that. That trial has completed its enrollment, is in follow-up, and hopefully by spring of 2020 we’ll have some results.

And so I think what that will do is take that gap between chronic therapy and acute post-revascularization for the limb and give us some information there. And hopefully if that shows similar trends, it will help us shorten the gap from when we know something works to getting it into our patients.

Deepak L. Bhatt, MD, MPH: Yes, that’s quite informative.

Transcript edited for clarity.