The Role of Factor Xa Inhibitors in the Management of CAD/PAD - Episode 5

Approaching Understandings of Antithrombotic Therapy

December 13, 2019

Deepak L. Bhatt, MD, MPH: I think that’s really a good point. Do you think it’s the same disease with respect to antithrombotic therapy?

John Eikelboom, MBBS, MSc, FRCPC: Well, it’s intriguing that as we start to do big trials and we start to see patterns of outcomes—and this is in antiplatelet trials and it’s in anticoagulant trials—we start to see that there are differences in the way that atherothrombosis manifests. For example, and this is a generalization, I personally think that in the coronaries, it’s somewhat more a platelet-driven process. And I wonder whether in larger vessels it’s also platelet driven, but more fibrin driven. And there are insights that we gained from mechanistic studies but also from clinical outcome studies.

Deepak L. Bhatt, MD, MPH: I think you’re on to something. There are at least some data from Jagat Narula, MD, PhD, published in the Journal of the American College of Cardiology, showing thrombus in lower extremities. And I don’t mean somebody who has AFib [atrial fibrillation] and a thromboembolism or a postmortem type of specimen, but rather an amputation specimen, signs of old thrombus, and then new thrombus forming on it, suggesting strongly that there’s a much more powerful role of thrombosis and recurrent thrombosis in peripheral artery disease [PAD] than we had appreciated before.

John Eikelboom, MBBS, MSc, FRCPC: And that was the study I was thinking of, Deepak. That’s just a beautiful study. As you recall, we found that in the more proximal vessels, there was atheromatous disease. But distally, some of these vessels were actually quite clean but with layer after layer of thrombus, implying embolism from more proximal sources. It’s intriguing, and we get into the whole story of stroke that looks to be embolic. Is it coming from the large vessels in the neck and the aorta? And should that be tackled with a combined anticoagulant and antiplatelet therapy?

Vamsi Krishna, MD: We see this when we do chronic total occlusions in the coronary artery and in the peripheral space, it’s interesting. The cap to cross it is calcified or it could be challenging. Once you cross it, actually when you’re in 100% occlusion, the wire easily goes. When I was a Fellow, and even now, I still get the joy of, oh, I crossed something difficult. But then when you start doing IVUS [intravascular ultrasound] and OCT [optical coherence tomography] inside there, you start to understand the pathology. And to your point, it’s full of thrombus. So the disease process is very interesting. For example, in the SFA [superficial femoral artery], when we’re dealing with these occlusions, there are a lot of experts now who will actually use various types of therapies out there, including sometimes using lytics inside the IVUS to understand the burden and do virtual histology. So the field is growing and our understanding is that it’s just not plaque, it’s a mixed composition.

Deepak L. Bhatt, MD, MPH: This is a classic case, actually, of what’s old is new because maybe 20 years ago among some interventional radiologists, that was a very common practice. You had a total iliac occlusion. I don’t mean an acute one, I mean a chronic one. They would cross, they would lyse overnight and then bring them back, and of course overnight lysis has fallen a bit out of favor these days, but it was the same concept.

Vamsi Krishna, MD: Exactly.

John Eikelboom, MBBS, MSc, FRCPC: Intriguingly, if this is true—and it is true, in theory at least—if we gave sufficient antithrombotic therapy of sufficient efficacy, we should be able to obliterate almost all acute events, and this is one of my great interests. Why is it that antithrombotic therapy is not more effective? Why is there a ceiling effect beyond which we just get more bleeding, but we can’t stop that thrombus? Is it the drivers of thrombogenesis that just cannot be suppressed, or is it that our antithrombotic therapies are not hitting the sweet spot, or are we targeting the wrong coagulation factors or the wrong pathway?

Manesh Patel, MD: I’m a simplistic person, but I think you’re right that the biology is likely somewhat different. I also think there’s an epidemiology and an evolutionary thing going on in that if you have atherosclerosis in your coronary artery and you rupture a plaque and you’re 50, unfortunately that’s a 3 mm vessel, and that thrombosis leads to a heart attack. If you’re that same person and you have a plaque in your superficial femoral artery or your common femoral artery, and that’s a 7 mm vessel or an 8 mm vessel, you then have this action where thrombosis might begin healing or going downstream to a smaller vessel and then healing because the amount of blood flow and the amount of ability to have collateral flow in that skeletal muscle rather than your cardiac muscle may be different.

Nevertheless, the flow characteristics and the ability to get the right amount of drug should be a way to distinguish and stop that. And I think in part, the newer therapies and some of the new science is telling us that. In the past, we had a blood agent in warfarin or just aspirin—I say just aspirin—but an antiplatelet therapy, and we kept using them because we had nothing else. And we used them in variations of patterns of patients who, as a clinician, get a benefit or don’t. And so I think one of the things we’re having to teach ourselves and learn with new therapies just like with the lipids is, what are the patterns of patients now that I can use this therapy in where I might get a bigger benefit because the risks aren’t the same as they might have been before.

And I think PAD is an example or carotid disease is an example of a patient that you should think about. In your clinic, how many patients do you have who have a 50% carotid, just because of however the ultrasound was done and somebody heard a bruit? It’s a lot. Aside from doing the things I usually do, I’m not sure I’d do much else because I’m not supposed to operate or do a stent—and stents are really less likely these days—until either they’re symptomatic or it gets a velocity of 500 or something that makes me really worry that I’m going to sleep and this person is going to call me.

Deepak L. Bhatt, MD, MPH: Those are good points. The fact about the carotid stenosis is a particularly interesting thing because there’s a lot of it out there. It doesn’t mean we should operate or stent it. But again, is someone in primary prevention if they’ve gotten a carotid ultrasound and there’s a 50% stenosis?

Manesh Patel, MD: Their risk is much higher. I think of it the same way as you said, which is a really great point. It’s a continuum. And along the continuum, it’s a 10-minute visit for a primary care doctor, or anybody. They’ve got 15 minutes. I keep talking about taking off their socks and shoes, but they say, “Look, I’ve just got to get the note in and make sure I get the right things done for this patient.” And so in that context, I would ask—and maybe we go around—what are the triggers that would make me think this patient is at higher risk?

Let’s say you have your prototypic patient who you think has prevention, we’ll just say broadly in the United States. In North Carolina, where I’m from, generally they might have hypertension and maybe some cholesterol, lipid problems. We’re trying to get him not to smoke, etc. What are the things that would make think this person is higher risk? Lack of pulses in the leg, a history of carotid disease, something with AAA [abdominal aortic aneurysm], anything in these areas that, before I even order a laboratory test, make me start to think that this is not that other patient that I have.

Deepak L. Bhatt, MD, MPH: And for the patient with athero you mentioned in passing, I think it’s important for our audience to really spell out the other things we talked about: cholesterol lower in general is better with respect to LDL [low-density lipoprotein] cholesterol achieved through diet; through statin therapy, ezetimibe; or if needed, bumping up therapy with more potent agents such as PCSK9 inhibitors. You mentioned smoking in passing, but of course, smoking cessation is really important for CAD [coronary artery disease], and in PAD as well, maybe even more important there. In those with diabetes, control their diabetes. In those with high blood pressure, control their blood pressure. So you want to make sure that those risk factors are well controlled. Diet, exercise, and lifestyle modifications are always a foundation of all that. But then when appropriate, use different types of pharmacotherapy.

John Eikelboom, MBBS, MSc, FRCPC: I like to think of it as a 3-legged chair. Cardiovascular prevention has got 3 pillars: lifestyle changes, risk factor modification, and antithrombotic therapy. And then if you’re on a really stable chair, you might get a fourth leg with 1 of the new ways to modify risk. But very simply put, I think for the family physician, do your risk stratification. Once you find that they need therapy, get those 3 pillars in place, and you will tailor your risk factor modification according to their risk profile and tailor the antithrombotic according to their risk profile. And everybody gets lifestyle modification.

Transcript edited for clarity.