Peripheral Arterial Disease: Lipid-Lowering Strategies

Transcript: Deepak L. Bhatt, MD, MPH: Let’s go back to medication, Marc. We talked about antiplatelet therapy. There’s monotherapy, there’s dual antiplatelet therapy. What about lipid lowering, whether it’s statins, ezetimibe, or PCSK9 inhibitors, the newest kids on the block?

Marc P. Bonaca, MD, MPH: That’s a great question. LDL [low-density lipoproteins] lowering appears to be very important for a patient with PAD [peripheral artery disease], just like the other patients with atherosclerosis. In the Heart Protection Study, there was a dedicated publication in the Journal of Vascular Surgery, which showed not only great benefit in cardiovascular outcomes but also a reduction in the need for repeat limb revascularizations, or PAD events. That was with a statin versus placebo.

More recently, as we’ve looked at achieving lower LDLs with the PCSK9 inhibitors, we’ve seen very important reductions in hard limb events with acute limb ischemia and amputation. We saw that in the FOURIER trial with evolocumab. It showed great benefits in MACE [major adverse cardiovascular events] and in limbs. In the ODYSSEY OUTCOMES trial—I know you were part of that study—there was a very nice analysis showing a reduction in PAD events and raising the question of whether LP(a) [lipoprotein(a)] is part of the equation. It’s not only LDL reduction, but maybe LP(a) reduction as well, with a PCSK9 inhibitor.

I think what we see in PAD with lipids is that PAD events, not only MACE events but limb events, appear to be very sensitive to these more intensive therapies. I think they’re an important part of the armamentarium because they’re safe. We know who to use them in. We know what people’s levels are, if you will. I think that intensive lipid modification will be critical in preventing events in patients with PAD.

I know you were involved with the REDUCE-IT trial, and with such phenomenal results I would expect that it is another therapy that will have profound benefits for our patients with PAD because of the risk profile and the benefits of the drug. I think lipid modification is got to be core in our preventive therapies for PAD.

Deepak L. Bhatt, MD, MPH: I agree with you. I think we want to get their LDL under control if they have PAD. We want to get their triglycerides under control. We want to get their blood pressure under control, too. There are some good data as well with respect to blood pressure control. Sometimes, I think doctors worry a little bit about if they are going to somehow decrease perfusion pressure. But in terms of reducing overall cardiovascular events, it’s a wise thing to get the blood pressure under control. Just to get back to LDL, what about PCSK9 inhibitors specifically? Do you want to talk about some of the work that you’ve done, Marc?

Marc P. Bonaca, MD, MPH: There have been 2 big trials with PCSK9 inhibitors that have reported PAD outcomes. In the FOURIER trial with evolocumab, there was a dedicated PAD subgroup. We looked at the risk of adverse cardiovascular and limb events. It was very interesting that the responsiveness regarding limb events was quite profound. If we think of LDL reduction, reaching normal per liter reduction in LDL results in about a 20% reduction in MACE; there, it seemed to be approximately

30% to 40% reduction in MACE alongside some other signals from other trials.

Evolocumab was very important in the PAD population regarding MACE and limb outcome. When you look at the different cohorts, even if you look at PAD alone without prior stroke or coronary disease or prior MI [myocardial infarction]—or at without patients known to have it—the affects look consistent regardless. I think those data were promising. More recently, in data just published out of the ODYSSEY OUTCOMES trial with alirocumab, we saw very similar findings with important reductions in PAD and VTE [venous thromboembolism] events.

I think what was really interesting about that analysis is it did show a relationship with LDL, but also with LP(a). Maybe LDL is not the whole picture with the PCSK9s. There could be additional benefit in these limb outcomes and VTE outcomes from reductions in LP(a), which of course is distinct from what the statins do.

Deepak L. Bhatt, MD, MPH: That’s really interesting. As you know, there was a signal of less VTE in JUPITER as well. It could be that not only PCSK9 inhibitors, but even high-potency statins in the right patient, may affect VTE. Mike, Marc has brought in this concept of LP(a) and how some of the benefits seen in peripheral events on FOURIER and ODYSSEY were due to LP(a) modulation. There are of course dedicated trials of LP(a) starting, and maybe you were even involved with some of them. What are your thoughts about that axis of risk reduction? Is there something there?

C. Michael Gibson, MS, MD: I think so. There’s bad cholesterol, and there’s LDL; but then there’s really bad cholesterol, and that’s LP(a). I think there are companies that are now coming forward with some very rapid tests of LP(a). I think it will be easier to test your patients for that. It does offer risk stratification compared to LDL. I do think it is going to be a viable biologic target. Of course, there are other randomized trials that are ongoing, and we’ll see if changing it alters those outcomes. It’s too early to tell.

Transcript Edited for Clarity