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Circulation on the Run


Dec 7, 2021

Please join Guest Host Mercedes Carnethon along with first author Connie Hess and Guest Editor Gregory Lip as they discuss the article "Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, our feature discussion is on a really important topic, peripheral artery disease. So important, so rampant, not talked about enough. And it's really insights from the VOYAGER-PAD trial telling us about the reduction in acute limb ischemia with Rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization. But before we get into all that, I want you to get your coffee while I tell you about my picks of today's issue. Should I start?

Dr. Greg Hundley:

Very good.

Dr. Carolyn Lam:

Okay. So the first paper deals with the residual ischemic risk following coronary artery bypass grafting surgery. We know that despite advances, patients following CABG still have significant risk. So this paper refers to a subgroup of patients from the REDUCE-IT trial with a history of CABG, which was analyzed to evaluate the efficacy of icosapent ethyl treatment in the reduction of cardiovascular events in this high risk patient population. Now, as a reminder, the REDUCE-IT trial was a multicenter, placebo controlled, double blind trial, where statin treated patients with controlled LDL cholesterol and mild to moderate hypertriglyceridemia were randomized to four grams daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint, which was cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Now the current report tells us about the subgroup of patients from the trial with a history of CABG.

Dr. Greg Hundley:

Ah, Carolyn. So what did they find in this subgroup of patients?

Dr. Carolyn Lam:

So of the 8,179 patients randomized in REDUCE-IT, 22.5% had a history of CABG with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between the treatment groups and randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint, as well as in key secondary endpoint and in total ischemic events compared to placebo. This yielded an absolute risk reduction of 6.2% in first events with a number needed to treat of 16 over a median follow up time of 4.8 years. So, Greg, I think you'll agree, icosapent ethyl may be an important pharmaco-therapeutic option to consider in eligible patients with a history of coronary artery bypass grafting surgery.

Dr. Greg Hundley:

Very nice, Carolyn. What an excellent summary. So Carolyn, for my first paper... And this study comes to us from Professor Judith Haendeler from the Leibniz Research Institute for Environmental Medicine. So Carolyn, this is a new type of quiz question. And as you listen to the presentation, help us predict the clinical implications. Okay, here we go.

Dr. Greg Hundley:

All right. So Carolyn, telomerase, also called terminal transferase, is a ribonuclear protein that adds a species dependent telomere repeat sequence to the three prime end of telomeres. And Carolyn, just to refresh our memories, a telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. And telomerase was discovered interestingly by Carol Greider and Elizabeth Blackburn in 1984. And together with some others, including Jack Szostak, they were awarded the 2009 Nobel Prize in physiology and medicine for discovery.

Dr. Greg Hundley:

So Carolyn, telomerase is active in gamuts and most cancer cells, but is normally absent from or at very low levels in most somatic cells. And the catalytic subunit of telomerase called telomerase reverse transcriptase or trt has protective functions in the cardiovascular system, particularly in regard to ischemia reperfusion injury. And interestingly trt or telomerase reverse transcriptase is not present in the nucleus, but also in mitochondria. However, for us in cardiovascular medicine, it is unclear whether nuclear or mitochondrial trt is responsible for the observed protection.

Dr. Carolyn Lam:

Wow, fascinating. So what did today's paper find?

Dr. Greg Hundley:

Right, Carolyn. So it was mitochondrial, but not nuclear telomerase reverse transcriptase that was found critical for mitochondrial respiration during ischemia reperfusion injury. And mitochondrial telomerase reverse transcriptase improves complex 1 subunit composition. And trt is present in human heart mitochondria and remote ischemic preconditioning increases its level in these organelles. Also, Carolyn TA65 was found to have comparable effects ex vivo and improved migratory capacity of endothelial cells and myofibroblast differentiation. So Carolyn, with this summary, can you help speculate on the clinical implications of this paper?

Dr. Carolyn Lam:

Oh, Greg. You set it up so nicely. So I would speculate that the clinical implications are that an increase in the mitochondrial telomerase reverse transcriptase or trt would be able to help with cardioprotection in ischaemic reperfusion injury, or at least that's what we hope and that's where we should be going with this. Am I right?

Dr. Greg Hundley:

Absolutely, Carolyn. So in the future, this research showing that trt and cardioprotection... Maybe we increase this and it could serve as a therapeutic strategy. Excellent job, Carolyn.

Dr. Carolyn Lam:

Thank you, Greg. All right. My next paper is a preclinical paper. I will spare you of difficult quizzes and maybe... This is just so neat. Let me tell you about it. So the study really provides novel insights into the mechanisms underlying smooth muscle cell phenotypic modulation that contributes to the development of vascular diseases like renal atherosclerosis and restenosis after angioplasty. So very important. Dr. Jiliang Zhou from Medical College of Georgia and colleagues basically used an in silico approach to probe unbiased, proprietary, and diverse, publicly available bulk RNA-Seq and scRNA-Seq datasets to search for smooth muscle cell specific long non-coding RNAs or lncRNAs.

Dr. Carolyn Lam:

The search ended up identifying CARMN, which stands for cardiac mesoderm enhancer-associated non-coding RNA, CARMN. As a highly abundant, highly conserved smooth muscle cell specific lncRNA, CARMN was recently reported to play roles in cardiac differentiation and was initially annotated as a host lncRNA for the microRNA, the MIR143145 cluster, which is the best characterized microRNAs in regulating smooth muscle cell differentiation and phenotypical modulation.

Dr. Carolyn Lam:

But in the current study, the authors confirmed the expression specificity of CARMN using a novel GFP knock-in reporter mouse model, and discovered that CARMN is downregulated in various vascular diseases. They further found that CARMN is critical for maintaining vascular smooth muscle cell contractile phenotype, both in vitro and in vivo by directly binding to the smooth muscle cell specific transcriptional cofactor known as myocardit.

Dr. Greg Hundley:

Okay. Carolyn, what a beautiful summary here. So what's the take home message here?

Dr. Carolyn Lam:

So these findings collectively suggest that CARMN is a key regulator of vascular smooth muscle cell phenotype, and therefore represents a potential therapeutic target for the treatment of smooth muscle cell related proliferative diseases.

Dr. Carolyn Lam:

Well, Greg, thanks for letting me to tell you about that one. But let me tell you also about other papers in today's issue. There's an exchange of letters between Dr's Lee and Chew on high rates of coronary events in the rapid troponin T0 one hour protocol. Is it a reality or illusion? There's an ECG Challenge by Dr. Liu on “Acute Inferior Wall Myocardial Infarction. What is the Culprit Artery? In Cardiology News, Bridget Kuehn writes on persistent heart effects of COVID-19 and how that emphasizes the need for prevention.

Dr. Greg Hundley:

Very nice, Carolyn. Well, I've got a Research Letter to tell you about from Professor Huang, entitled “High Prevalence of Unrecognized Congenital Heart Disease in School-Age Children in Rural China: A Population-Based Echocardiographic Screening Study.” Well, Carolyn, what a fantastic issue. And how about we get onto that feature discussion now and learn more out lower extremity revascularization and insights from the VOYAGER-PAD study?

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Mercedes Carnethon:

Good morning, everyone. Welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and associate editor of the journal. Really excited today to hear from one of our authors of a particularly interesting piece that we'd like to discuss today about peripheral artery disease after lower extremity revascularization.

Dr. Mercedes Carnethon:

And we have with us today, the lead author, Dr. Connie Hess from the division of cardiology at the University of Colorado School of Medicine in Aurora. And we have Dr. Gregory Lip with us. So welcome to the both of you.

Professor Gregory Lip:

Hello there.

Dr. Connie Hess:

Thank you for having me.

Dr. Mercedes Carnethon:

Thank you both for joining us. This is really exciting. I know that when I read this piece, I was really excited to think about the implications that these study findings from this clinical trial will have for a very important clinical problem of peripheral arterial disease and those complications. So, Connie, would you be willing to start by telling us a little bit about what you found in this study?

Dr. Connie Hess:

Yeah, absolutely. I think maybe a good place to start first is, if that's okay, is just a little bit of the background and why we looked at this and thought to look at this. I think as you're both probably aware, peripheral artery disease is a very highly prevalent condition. It affects a lot of people, but there's not a lot of awareness about it. It's in some ways the forgotten manifestation of atherosclerosis. And so acute limb ischemia in particular is a very feared complication of peripheral artery disease. And unlike things like ST elevation, myocardial infarction, and stroke about which patients and providers have a lot of knowledge and understanding, many people don't know about acute limb ischemia. And in particular ALI, acute limb ischemia, is a complication of peripheral revascularization that many of us as proceduralists are very concerned about.

Dr. Connie Hess:

And so what we wanted to do was use this very unique clinical trial and dataset to look at acute limb ischemia, to describe it, to better understand it, especially after a peripheral revascularization. And then also to look at the effect of Rivaroxaban plus aspirin versus aspirin alone on this feared outcome. We're lacking therapies to effectively prevent ALI.

Dr. Connie Hess:

And so if I just briefly review the trial, VOYAGER-PAD randomized 6,564 patients undergoing peripheral revascularization, both surgical or endovascular to Rivaroxaban, 2.5 milligrams twice daily versus placebo on top of aspirin. And then providers could use prochidagril for up to six months per their discretion. Now, the primary outcome for VOYAGER-PAD was very unique. This was a five point composite that looked at acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death.

Dr. Connie Hess:

And so in this trial in the primary results, Rivaroxaban plus aspirin versus aspirin alone was highly effective in reducing the primary endpoint, that five point composite I just described. And so we were excited to look specifically at the effect of this combination therapy on acute limb ischemia alone. What we found to begin with, I think in terms of describing acute limb ischemia is important. So the three year cumulative incidence in the patients assigned a placebo was about 8% for ALI. So this is not an uncommon problem. And in fact, we found that there was incidents of ALI occurring quite early after the procedure and that the risk persisted, even three years out.

Dr. Connie Hess:

And Rivaroxaban plus aspirin versus aspirin alone was very effective in reducing ALI by about 33%. Beyond that, we also looked at ALI in terms of severity of these complications. And we found that about a third of patients had a very severe ALI event that we defined as ALI followed by death, major amputation, or requiring a prolonged hospitalization with time in the intensive care unit. And for those patients, Rivaroxaban plus aspirin was even more effective with almost a 55% reduction.

Dr. Connie Hess:

Lastly, I think we also looked at just the patients who are at risk for ALI after peripheral revascularization. And we did identify some patient and procedural factors that might help us identify these patients. For example, having a prior lower extremity revascularization, having more severe PAD as indicated by a low ankle brachial index, undergoing surgical revascularization, and having longer target lesions. So I think we were able to describe ALI in a way that some other trials and datasets have not been able to do. And then also beyond that to provide some evidence for effective therapy to prevent this complication.

Dr. Mercedes Carnethon:

All of that is so exciting. And for somebody coming to this outside of the initial field, I can certainly see a lot of innovations that you describe in what you've done and the importance to the population of people who experience this very debilitating illness. So it's really wonderful to see this in print. So tell me, Greg, what excited you as the editor about this particular paper? So what made it really stand out in your mind?

Professor Gregory Lip:

Thanks, Mercedes. And firstly, congratulations to Dr. Hess for a really nice paper. And I think that it's really important because many cardiologists tend to neglect looking at and managing peripheral artery disease, especially with the medical therapies. And I think VOYAGER-PAD was an important advancement of how we can have... You could say, dual blockade, both with low dose anticoagulation plus antiplatelets should improve the outcomes.

Professor Gregory Lip:

So I think it really brings to the forefront how we should optimize medical therapy and peripheral disease. It's not simply a matter of surgery or just intervention with stenting. And I think maybe the other important aspects in regard to this study, this trial is when you combine an antiplatelet with an anticoagulant, it's worth flagging up the potential for added risk of bleeding. And it's therefore the fact that your analysis included to identify the patients at high risk of acute limb ischemia, then we will actually facilitate risk stratification so that we can perhaps target the very high risk patients where that balance in terms of the net benefit for the combination therapy compared to aspirin alone would be there because you're balancing the thrombotic and limb ischemic outcome versus the potential for bleeding.

Professor Gregory Lip:

We are also using of course, in VOYAGER-PAD low dose Rivaroxaban, which is not the stroke prevention dose of Rivaroxaban in everyday clinical practice. And that's worth emphasizing. So we translate peripheral disease dosages or regimes versus what we see in other prothrombotic situations like atrial fibrillation, which leads to stroke. And that's probably worth emphasizing. And I think really what is most important is that we can hopefully identify the high risk subset of patients with peripheral artery disease at risk of acute limb ischemia, where they're going to particularly benefit from combination therapy. So an important advance for medical therapy for peripheral disease. So congratulations on this paper as well.

Dr. Mercedes Carnethon:

Yeah. I really echo that. One of the things that when we write original research papers, we are always encouraged not to speculate beyond the data that we're presenting. But one of the values of this podcast is that we get a chance to really needle the authors and challenge them to speculate about what does this mean? What does this mean for the field? And Connie in particular, what do you think the next steps are for patients and providers based on what you found today in this excellent study?

Dr. Connie Hess:

Mercedes, that's a great question. Certainly we always want to know what next? What are the implications of these findings? And so to me, I echo both of you. I'm personally very excited as someone in the field. And as a proceduralist, I'm very excited that for the first time, we actually have data to support a medical therapy post intervention. Although there's a lot of use of things like dual antiplatelet therapy and even anticoagulation, there's not a lot of data to support it after peripheral revascularization. So this really is the first large scale, high quality data to support a strategy. And so I do think that this is something that we should adopt.

Dr. Connie Hess:

I think what I didn't mention before is that actually, when you look at the cumulative incidence curves for ALI in the Rivaroxaban versus placebo groups, not only do you see that there is early risk for ALI after the procedure... And typically we think of this as potentially technical failure that we can't modify, but you saw a very early benefit for Rivaroxaban plus aspirin versus aspirin alone here, suggesting that the sooner you start, the better. Of course, it has to be when it's safe from a bleeding perspective and when the proceduralist feels comfortable with this. But I do think that the implications are that we should... We proceduralists, especially in this population and as professor Lip mentioned the high risk patients in particular, should be starting this therapy as soon as we feel safe. And so I think the data are there. The next step to me is really increasing awareness, in particular among providers who are treating these patients, but even among our other colleagues or cardiovascular colleagues who may not treat these peripheral artery disease patients primarily, but do see them in their clinic.

Dr. Connie Hess:

A lot of them have cardiovascular disease and other cardiovascular problems, but to increase awareness that this dual pathway inhibition with low dose factor 10, anticoagulation inhibition and low antiplatelet therapy is a viable and favorable combination and to continue this so that when they see this, they're not surprised and not questioning whether to stop it.

Dr. Connie Hess:

I think also of course now that we are getting more data to understand how morbid and bad ALI is, I do think we also need to educate patients. You both probably recall all the tremendous efforts that were made to increase awareness in the patient population about myocardial infarction and stroke. You have all those campaigns and understanding the importance of timely intervention and reperfusion. I think that actually should be done for acute limb ischemia as well. We need to have providers aware about this complication and understanding emergent treatment. We also need patients to understand it so they can come in sooner so that they're not having delayed presentation for which primary amputation is the only treatment option. So I think there's a lot of work to be done, but certainly very excited that we have a better understanding of ALI as well as preventive therapy.

Dr. Mercedes Carnethon:

I really appreciate that final word. And I really can't think of a better way to wrap up than the final words that you provided, Connie. Both the context that you provided around this piece and your thoughts as well, Greg, about what makes it innovative and exciting for our readership at Circulation are really invaluable. So I just really want to thank you for joining us as an author and thank you for selecting this, Greg. This is a really great piece. I've learned a good deal.

Dr. Mercedes Carnethon:

This is me, Mercedes Carnethon, wrapping up this addition of Circulation on the Run, following an outstanding discussion with Dr. Connie Hess from the University of Colorado and Greg Lip, the handling editor for the piece.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.