Activity Transcript

Charles P. Vega, MD: Hello and welcome to this episode in our PAD-TV series, which will discuss ‘Managing Peripheral Artery Disease Post-Revascularization: Translating New Data into Practice’. I’m your host, Chuck Vega, Clinical Professor of Family Medicine at the University of California Irvine.

Patients with PAD can experience claudication, atypical leg symptoms, critical limb ischemia, or acute limb ischemia. Peripheral artery revascularization is commonly performed in patients with claudication to improve symptoms and quality of life. In those with critical or acute limb ischemia, revascularization is vital to relieve ischemic pain, improve wound healing, and prevent amputation.

Yet despite these benefits, patients who have undergone lower extremity revascularization are at high risk for both major cardiovascular events and major adverse limb events, including amputation.

In today’s program, we’re talking to Dr Joshua Beckman, Professor of Medicine and Director of Vascular Medicine at UT Southwestern in Dallas, Texas. Dr Beckman is going to help us understand how we can reduce the risk of major cardiovascular and limb events following lower limb revascularization.

Dr VEGA: Hello Dr Beckman, thank you for joining us today.

Joshua Beckman, MD: You’re welcome.

Dr Vega: We know that patients who have undergone revascularization due to PAD are at especially high risk for major thrombotic events. What do we know about the magnitude of this risk?

Dr Beckman: It has been estimated that patients with PAD who undergo peripheral revascularization are approximately 4 times more likely to experience subsequent vascular complications compared with those who have never undergone revascularization. A large observational analysis of almost 400,000 patients with PAD who underwent peripheral artery revascularization found that, during a median follow-up period of 2.7 years, they had a 9.8% incidence myocardial infarction or stroke, and a 41.9% incidence of revascularization or amputation.

Dr Vega:

Do we know why patients who have undergone revascularization have such a significantly elevated risk for these serious events?

Dr Beckman:

There haven’t been a lot of studies exploring this issue. In some cases, the risk may be magnified by individual patient characteristics – for example, many patients undergoing revascularization have atherosclerotic disease in more than 1 vascular bed. And a significant proportion do not receive optimal therapy either before or after undergoing the procedure. But it’s also likely that the mechanical disruption of the endothelium and the resulting inflammatory activation that occur during revascularization contribute to the risk of future events.

Dr Vega:

So, you’re saying that the underlying pathophysiology may be different in these patients?

Dr Beckman:

Yes, there’s now good evidence to support that. You know, until quite recently it was generally assumed that the pathology and plaque composition of lower extremity arteries in PAD patients is similar to the pathology of atherosclerosis in the coronary and carotid arteries. We now know that is not the case. In the central circulation, major thrombotic events tend to be the result of platelet adhesion, activation, and aggregation, terminating in plaque rupture.

In the peripheral circulation, however, the process has been found to be one of progressive occlusive disease and narrowing of arteries in the lower extremities. In addition to increased platelet activation, PAD patients typically have changes in fibrinogen levels, thrombin generation, and fibrin turnover. When somebody reaches the point that they require revascularization to resolve critical limb ischemia, their PAD has become very severe. So, if you look at their arteries, you’re going to see a high degree of thrombotic occlusion and medial calcification, particularly in the arteries below the knees.

DR Vega:

Antiplatelet therapy has been a cornerstone of PAD treatment for more than 2 decades now. The most recent AHA/ACC Guideline recommends aspirin alone at a dose of 75 to 325 mg per day, or clopidogrel alone at a dose of 75 mg per day, to reduce the risk of myocardial infarction, stroke, and vascular death in patients with symptomatic PAD. Even in the absence of symptoms, the guideline advises that patients with PAD are at increased cardiovascular risk, and antiplatelet therapy is therefore reasonable.

Dr Vega:

Although antiplatelet therapy for PAD has been well established for quite a long time. How effective are these medications?

Dr Beckman:

Antiplatelet therapy has been a cornerstone of the treatment of PAD now for decades, and the cardiovascular benefits have been established by many different studies. The first big study in this area was CAPRIE in 1996, comparing aspirin alone versus clopidogrel alone in around 19,000 people with coronary disease, stroke, and peripheral artery disease. It demonstrated, in the aggregate, a relative risk reduction in terms of cardiovascular events of about 8% in the clopidogrel arm compared with the aspirin arm. So clopidogrel was superior. Less bleeding was also seen with clopidogrel than with aspirin.

But in an unplanned hypothesis-generating secondary endpoint, clopidogrel seemed to have an outsized benefit in peripheral artery disease compared to the other beds, with a 23.8% relative risk reduction.

So clopidogrel was approved as monotherapy for each of the vascular beds on the basis of CAPRIE.

Since then, both aspirin and clopidogrel have been recommended for antiplatelet therapy in patients with PAD, initially and primarily to reduce the risk for cardiovascular events, rather than reduction in limb endpoints like claudication and amputation. Antiplatelet agents are clearly beneficial for improving cardiovascular outcomes in patients with PAD, but as far as we know, they do not do anything for limb events.

Dr Vega:

Now, ticagrelor is a newer antiplatelet agent with a similar mechanism to clopidogrel – they both inhibit ADP binding to the P2Y12 receptor. Does this agent offer any advantages?

Dr Beckman:

Not really. There was a comparison between ticagrelor and clopidogrel in patients with PAD called the EUCLID trial. One thing that is clear is that some people appear to be less sensitive to clopidogrel. But in EUCLID, they made sure that everybody was perfectly sensitive to clopidogrel and then compared it to ticagrelor, and there was no difference in outcomes. So, I would say there's no evidence that it matters which P2Y12 inhibitor you're using, as long as you're using it in addition to a baby aspirin of 81 milligrams in the United States.

Dr Vega [to Dr Beckman]:

Dual antiplatelet therapy has been shown to reduce the risk of major cardiovascular events in some patients with CAD, and it’s often used, therefore, in patients with PAD. But there seems to be uncertainty about the value of this approach. How much of an effect does dual antiplatelet therapy have on outcomes in PAD?

Dr Beckman:

Well, as you say, dual antiplatelet therapy is commonly used in PAD. But when you look at the evidence base, there isn’t really much of a case for combining antiplatelet agents. The most common situations where dual antiplatelet therapy tends to be used are after intervention, in the setting of difficult surgery, or in someone who has already had a coronary intervention and has polyvascular disease. But a couple of trials looked at the effects of dual platelet therapy on outcomes. Neither of them really reached a conclusion, but neither of them demonstrated any benefit either. So, when the guidelines committees looked at the data, they determined that there simply isn’t enough evidence to support any benefit from DAPT in PAD, and there is the potential for increased bleeding.

Dr Vega:

Antiplatelet medications are not the only proven approach to prevention of arterial thrombosis – anticoagulants have also been shown to be very effective for preventing myocardial infarction and stroke in patients with coronary artery disease. Thrombus formation is a complex web of pathways that involves not only platelet activation and aggregation, but also fibrin generation. Antiplatelet agents and anticoagulants control different steps within this system. Whereas aspirin, clopidogrel, and ticagrelor inhibit platelet aggregation, warfarin and the newer direct oral anticoagulants – apixaban, edoxaban, rivaroxaban, and dabigatran – inhibit fibrin generation.

Dr Vega:

Why haven’t anticoagulants played a central role in the treatment of PAD?

Dr Beckman: That’s a great question. We know that dysregulation of procoagulant, anticoagulant, and fibrinolytic pathways contribute to arterial and venous thrombosis in   patients with PAD, so you would expect anticoagulants agents, which inhibit these pathways, to be beneficial. And, in fact, there was a thought that maybe intermediate dose anticoagulation with warfarin (with an INR of 2 to 3) plus a baby aspirin may be superior to baby aspirin alone in patients with PAD. There was some evidence that this regimen was helpful in coronary artery disease, and it was therefore tested in the WAVE trial. Unfortunately, the addition of warfarin provided no benefit in terms of either cardiovascular or limb events, and there was an excess of intracranial hemorrhage. So current PAD guidelines, which are based primarily on the results of studies with warfarin, have not recommended use of anticoagulant therapy to reduce cardiovascular events in PAD. Whether anticoagulation may help improve patency after revascularization, however, has been less clear cut until now.

Dr Vega:

What has changed?

Dr Beckman: Two trials have shown that we can, in fact, further reduce the risk of cardiovascular and limb events in PAD by adding a low-dose oral anticoagulant. The first of those studies – COMPASS – looked at the effects of adding the factor Xa inhibitor, rivaroxaban, in more than 27,000 patients with stable atherosclerotic vascular disease. Most of the subjects had coronary artery disease, but around 27% had PAD or both. All of the subjects were randomized to receive aspirin alone, aspirin and what I'll call ‘arterial dose’ rivaroxaban at 2.5 mg twice daily, or rivaroxaban 5 mg alone twice daily. The trial was ended early, after a mean follow-up of 23 months, because the combination of aspirin and the arterial dose rivaroxaban demonstrated significant benefit very quickly in the reduction of cardiovascular events and limb events.

Dr Vega: Based on those numbers, almost 7,500 patients in the study had PAD. What can you tell us about the severity of disease in those individuals?

Dr Beckman: There was quite a diverse range of PAD severity, ranging asymptomatic disease to intermittent claudication, previous revascularization, and even prior amputation. When you look specifically at the results in that group, you see that they actually did even better than the overall study population. Addition of the 2.5-mg dose of rivaroxaban reduced major adverse cardiovascular events by 28% compared with aspirin alone, and reduced major adverse limb events by 46%.

Dr Vega: So, by adding an anticoagulant on top of the usual antiplatelet drugs, a large reduction in serious events due to PAD was achieved over a relatively short period of time…

Dr Beckman: Yes, those results were really quite exciting – what we now had was a medication that reduced not only cardiovascular events, but also the rates of major adverse limb events, including even those small numbers of amputations. 

And then the second important study was VOYAGER-PAD, which looked at outcomes in a high-risk population of 6,564 patients with PAD who had undergone revascularization, either surgically or percutaneously.

This was a 2-arm study – either aspirin plus rivaroxaban 2.5 mg twice daily or aspirin alone. And again, patients who received both aspirin and rivaroxaban had a significantly lower incidence of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, and death from cardiovascular causes.

Dr Vega:

Let’s talk about the rivaroxaban dose. The ‘arterial dose’ of 2.5-mg twice daily is much lower than the 10 mg a day that is used as in the hospital to prevent venous thromboembolism, or the 20 mg daily that we would prescribe for venous thromboembolism or atrial fibrillation.

Dr Beckman:

Yes, it's really interesting that you only need a very small dose to derive this benefit. Modulating factor Xa at a very low level seems to have particular benefit that I don't really think is well explained yet. I can tell you that it works because it's been studied and we have the data to show that it works. But I think we're still trying to figure out the exact mechanisms by which very different dosing with factor Xa inhibitors yields very different results.

Dr Vega:

One of the things that physicians often worry about when prescribing an anticoagulant, of course, is the possibility of serious bleeding. Was that a problem in these studies?

Dr Beckman:

In clinical practice, we tend to be very cautious about prescribing anticoagulants in patients who are at high risk for bleeding, and both studies therefore excluded these patients. Although there was some more bleeding – as there always is when you add antithrombotic agents – there was really no difference in intracranial hemorrhage or fatal bleeding. Although bleeding is an important consideration, in most cases I think it's quite manageable, and you want to be able to avoid things like acute limb ischemia and other severe limb outcomes. So, the net clinical benefit was clearly in favor of prescribing rivaroxaban and reducing all the cardiovascular and limb adverse events. Conversely, although VOYAGER wasn’t designed to test the duration of clopidogrel therapy, there was no difference in limb outcomes if you gave clopidogrel for more than or less than 30 days. Therefore, to avoid any unnecessary bleeding risk, I would generally minimize the exposure to triple therapy if I could by trying to stop clopidogrel after 30 days.

Dr Vega:

Have other oral anticoagulants also been shown to be beneficial in PAD?

Dr Beckman:

Not at the moment. In the APPRAISE-2 study, addition of the factor Xa inhibitor, apixaban, did not reduce the rate of ischemic events following an acute coronary syndrome. However, the dosing was not comparable, so they may not have found the right dose. Or there may be a mechanism that is unique to rivaroxaban. We  really don't know yet because the studies haven’t been done. The antithrombotic agent vorapaxar, which inhibits platelet aggregation, was approved for use with aspirin and/or clopidogrel to lower the risk of major cardiovascular events. The data suggest that it may have some benefit in terms of limb events. But it hasn’t been directly tested, and I think that this particular agent has largely fallen by the wayside at the moment. So for now, the evidence that we have tells us that the most effective antithrombotic strategy in PAD – particularly in those high-risk patients who have undergone revascularization – is an antiplatelet agent plus rivaroxaban at its lowest dose of 2.5 mg twice daily.

Dr Vega:

On that note, I would like to thank you for what has been a truly interesting conversation

Dr Beckman: It was great speaking to you.

Dr. Vega:

As always, we hope that you found this program informative and that you are able to apply these insights in your own clinical practice. Please continue on, to answer the questions that follow and complete the evaluation. And be sure to join us again for the next episode, in which we will be talking about ‘Integrating VTE Prevention Strategies Across the Care Continuum’. Thank you for watching today – goodbye for now.

This transcript has not been copyedited.