PAD Treatment Options

EP: 1.Peripheral Artery Disease (PAD) Pathophysiology and Coronary Artery Disease

EP: 2.Risk Factors for PAD Development

EP: 3.Diagnosing PAD

EP: 4.Challenges in Identification of PAD in Health Systems

EP: 5.PAD Management Strategies

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EP: 6.PAD Treatment Options

EP: 7.COMPASS Trial

EP: 8.The VOYAGER PAD Trial

EP: 9.Management of Major Adverse Limb Events in PAD

EP: 10.Improving Outcomes in PAD

Christopher Granger, MD: There are 2 things I’d like to mention, one is back to the high intensity statin. Ironically, high intensity statins, from our work with HealthCore-Anthem…and the Sentinel database, for patients with PAD [peripheral artery disease], high intensity statins are used less than for coronary disease. Less than 20% of the broad population with a claims diagnosis of PAD in the Anthem data is on a high intensity statin. That’s low hanging fruit to improve that.

Larry Allen, MD:The other thing is, not only are they cheap, but they’re well tolerated, and they improve symptomatology. Amr said that it’s important that we talk about future death, and people don’t conceptualize that, but some of these therapies can improve walk distance and peoples’ quality of life. Some of the things we’re talking about, including hypertension control, statin, exercise, and quitting smoking; some of those benefits can happen quickly. If people can see and feel that, then that’s another piece of this, which is trying to work on things that aren’t torture. They are giving short- and long-term benefit.

Amr Abbas, MD:Another important thing that we don’t frequently talk about, but we touched on in heart failure, is cilostazol. It’s a class 1 recommendation, except if you have heart failure, but it improves your walking distance and decreases walking pain by 50%. We’re not quite sure how it works, but nevertheless it seems to work. This is again low hanging fruit that we can touch on and improve the quality of our patients.

Manesh Patel, MD:Those are great points. I’ll say a couple of things from the purist model, but I agree we should be getting our patients on statins. Let’s get them on statins and then high intensity statins; 50% are not on statins. This is where the internet sometimes gets you because patients will come in and say, “That medicine makes your legs hurt, it causes muscle aches, I’ve got leg aches anyway, am I supposed to take that?” And I must to prove to them that they are supposed to. That’s No. 1. No. 2, cilostazol, a walking program, is great. All of those are right. The guidelines recommend walking, risk factor reduction, and smoking cessation, but the biggest change, maybe not evident to everyone, is a conversation and a change that has occurred around antiplatelet, antithrombotic therapy. It’s an important message because this is where my thinking started to change on PAD versus CAD [coronary artery disease]. Amr, can you discuss antiplatelet therapy with PAD? What do we know about that in vascular disease? And then we’ll take a moment to think about anticoagulation strategies and why we are thinking about those, because it might feel a bit out of step with what will happen in the coronary world. Amr, can you want to start with the antiplatelet? As interventionists, you and I are probably wed to antiplatelet therapy, since we put metal in place, so tell me about antiplatelet therapy.

Amr Abbas, MD:The initial and most famous antiplatelet therapy is aspirin. The first study that tried to see if aspirin or Plavix [clopidogrel] were better was the CAPRIE trial, where they compared patients in 3 buckets, cerebrovascular, CAD, and PAD. They noted in the PAD group that Plavix was better than aspirin by a marginal 8% reduction, so that’s where Plavix got its approval for patients with PAD. But if 1 agent is better, are 2 agents better? More is better, right? The next studies looked at the combination of aspirin and Plavix, the CHARISMA trial, versus aspirin alone. It doesn’t matter how they sliced and diced it, it increased the bleeding but didn’t translate into an outcome. When you have a population like you mentioned earlier of 200 million patients, and a $4 billion a year cost in the United States, then everybody wants to get into it. There are studies looking at ticagrelor and comparing that to aspirin, or comparing it to Plavix. They all didn’t pan out as we would have expected in terms of outcomes. The antiplatelet therapy has boiled down to either aspirin or Plavix, unless you get a revascularization. That is where we can shift into what we’re going to talk about later, which is the resurgence of this interest in anticoagulation therapy post revascularization of PAD.

Manesh Patel, MD:That’s great. Chris, what is your take on this? You’ve been part of the antiplatelet ACS [acute coronary syndrome] story for a long time. Until recently, all the PAD guidelines are subgroups, so even the PAD indication that clopidogrel has was a subgroup of the CAPRIE trial. CAPRIE is a big study, but it’s not much different than COMPASS, which we’ll talk about in a second with low dose rivaroxaban, or VOYAGER’s interventional study. How do you put it into the concept of what we’re learning about dual antiplatelet therapy [DAPT] and mono antiplatelet therapy in chronic vascular disease, not acute coronary syndrome?

Christopher Granger, MD: There has been an appreciation and an evidence generation that dual antiplatelet therapy long term for most patients has a risk that is as great as the benefit. Therefore, long-term DAPT, there’s some room for personalization of that, but generally, less intense antiplatelet therapy, for example with clopidogrel alone [may be better]. Sometimes with ticagrelor alone, following 3 months after stenting, for example, is a good option. But I think deintensification of the antiplatelet therapy for all vascular diseases has happened.

Manesh Patel, MD:My perspective, when we started the EUCLID trial, which was going to be the first large PAD trial outpatient, we thought we had the platelet hypothesis. It’s a vascular disease and leads to atherosclerosis and inflammatory atherothrombotic disorder. We’re going to affect the thrombotic end of this. We’ve talked about how to reduce the inflammation, how you do the lipids. And the antithrombotic part, we said you put a coronary stent in. You use more antiplatelet, the data for ACS seem to be better, although chronically, the DAPT trial was ongoing. We didn’t know it at the time. We did know that over time dual antiplatelet therapy with ticagrelor and aspirin had some bleeding. We wanted to learn, so we went monotherapy ticagrelor versus clopidogrel, thinking that it would be straightforward to beat clopidogrel for a MACE [major adverse cardiac event] end point, 14,000 patients. You must change your way of thinking about biology when the Kaplan-Meier curves are right on top of each other, there’s no difference, and you’ve spent 5 years doing it. You sit in a room and go, maybe we don’t understand the disease as much as we think we do. That led me to realize that more antiplatelet therapy chronically in patients with vascular disease has not been dramatically effective at reducing limb events, much less coronary events, remembering that patients with PAD, only a third of them have coronary disease that’s clinically evident. They somehow got to age 65, 70 with a bunch of vascular disease without having a heart attack; there’s sometimes something else going on.

Larry Allen, MD:Before we move on, I would ask you, one of the areas of minor disagreement between the European guidelines in 2017 and the American guidelines in 2016, is whether aspirin is equivalent to clopidogrel and whether there’s a preference. I’m curious about your thoughts and how it’s changed over the last 5 years.

Manesh Patel, MD:This is the first time the Europeans and Americans disagree on the guidelines. It won’t be the last, but unlike the Ryder Cup, it’s not as much fun. People don’t want to say it in the guidelines, but it was all based on cost. You had a 19,000-patient study in the late 1990s, early 2000s, the CAPRIE trial, that looked clopidogrel versus aspirin. You may not like the fact that it was 8% better, but it was 8% better in all vascular disease, so saying they’re equal is untrue. Now, the value of aspirin might have been better. Jeffrey Berger, [MD,] and others did a meta-analysis of aspirin in all the PAD trials, and only in the PAD population by itself did aspirin seem to be effective. The Europeans take that very much at face value. They are in a system where clopidogrel and aspirin are potentially not as driven by a cost differential, so they ranked them similarly. If you look at them now, one would have to argue that clopidogrel is still probably better than aspirin, in fact we just did a big PAD trial that showed it’s similar to ticagrelor. You can’t say they’re all the same, there are differences in efficacy, but it just happens that the 2 on the higher end didn’t change enough in these stable outpatients.

This transcript has been edited for clarity.