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Circulation on the Run


Nov 21, 2022

This week, please author Jung-Minh Ahn and Associate Editor Emmanouil Brilakis as they discuss the article "Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-Up Outcomes of Multicenter Randomized Controlled BEST Trial."

Dr. Greg Hundley:

Welcome, listeners to this November 22 issue of Circulation on the Run. And I am Dr. Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway, and also a social media editor interpolation.

Dr. Greg Hundley:

Well Peder, our feature this week, we are reviewing a comparison between drug eluting stents and bypass surgery for multi vessel coronary artery disease. Really an extended follow up from the Vest trial.

Dr. Peder Myhre:

I can't wait, Greg.

Dr. Greg Hundley:

Right. But before we get onto that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first?

Dr. Peder Myhre:

Sure, I'd love to. And the first paper today is a clinical one and it is entitled, “Efficacy of a Drug Eluting Stent Versus Bare Metal Stents for Symptomatic Femoropopliteal Peripheral Artery Disease: Primary Results of the Eminent Randomized Trial.” And it comes to us from the corresponding author Yann Gouëffic from Groupe Hospitalier Paris St. Joseph in France. So Greg, a clear patency benefit of a drug eluting stent over bare metal stents for treating peripheral artery disease of the femoropopliteal segment has not been definitely demonstrated. But today's paper publishes the primary results of the eminent randomized trials, which was designed to evaluate the patency of the Eluvia drug eluting stent. And this stent is a polymer based paclitaxel eluting stent and it was compared with bare metal stents for the treatment of femoropopliteal artery lesions. In fact, with 775 patients, Eminent is the largest randomized trial of drug eluting stent treatment for symptomatic femoropopliteal arterial disease to report patency to dates.

Dr. Greg Hundley:

Very nice, Peder. So describe for us, what were the results of this very large randomized clinical trial?

Dr. Peder Myhre:

Sure, Greg. So the primary effectivity outcome was primary patency at 12 months, defined as independent core laboratory assessed duplex ultrasound peak systolic velocity ratio less than or equal to 2.4 in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesions. And primary effectiveness analysis from the Eminent randomized study demonstrated superior one year primary patency for the Eluvia drug eluting stent versus bare metal stent. And that is 83.2% versus 74.3% with a P value less than 0.01. And this treatment was associated with a greater incident of Rutherford classification improvement without the need for re-intervention, and functional parameters demonstrated improvements in both groups, and there were no statistical difference observed in one year mortality between patients treated with the Eluvia drug eluting stents and bare metal stents. So in summary, this high level evidence supports the one year benefit of polymer based paclitaxel elusion over bare metal stents to treat superficial femoral artery and/or proximal popliteal artery lesions. What'd you think of that, Greg?

Dr. Greg Hundley:

Very nice. So sounds like for peripheral arterial interventions, a benefit from the polymer based paclitaxel eluting stents.

Dr. Peder Myhre:

Exactly. And there's also an editorial putting these results in context from Doctors Mosarla and Secemsky entitled, “From Imperialism to Eminence: The Noble Rise of the Second Generation Peripheral Drug Eluting Stents.”

Dr. Greg Hundley:

Excellent, Peder. Well, my article comes to us, Peder, from the world of preclinical science. And Peder, these investigators led by Professor Volker Spindler from University of Basel evaluated arrhythmogenic cardiomyopathy. And as you know, arrhythmogenic cardiomyopathy is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life threatening arrhythmias. So a substantial proportion of arrhythmogenic cardiomyopathy is caused by mutations in genes of the desmosomal cell to cell adhesion complex, but the underlying mechanisms are not well understood. So to address this, the team mutated the binding site of desmoglein two, a crucial desmosomal adhesion molecule in cardiomyocytes. This desmoglein two W2A mutation abrogates the tryptophan swab, a central interaction mechanism of desmogenin two based on structural data. Now, the impaired adhesive function of this DSG2W2A was confirmed by cell to cell dissociation assays and for spectroscopy measurements by atomic force microscopy.

Dr. Peder Myhre:

Wow. We continue to learn more about this disease, arrhythmogenic cardiomyopathy. And this sounds so interesting. Greg, please tell me what did they find?

Dr. Greg Hundley:

Right, Peder. So they found that the DSG2W2A mutation impaired binding on the molecular level and compromised intercellular adhesive function. Now, mice bearing this mutation, developed a severe cardiac phenotype recalling the characteristics of arrhythmogenic cardiomyopathy including cardiac fibrosis, impaired systolic function, and arrhythmia. Now, a comparison of the transcriptome of the mutant mice with arrhythmogenic cardiomyopathy patient data suggested deregulated integrin alpha V beta six and subsequent TGF beta signaling as a driver of cardiac fibrosis. Now accordingly, blocking integrin alpha V beta six led to reduced expression of pro-fibrotic markers and reduced fibrosis formation in the mutant animals in vivo.

Dr. Peder Myhre:

Oh, this is so important mechanistically. And Greg, can you please tell us something about the clinical importance of these findings?

Dr. Greg Hundley:

Right Peder, just like Carolyn always driving at that clinical significance. So these authors show now that disruption of desmosomal adhesion is sufficient to induce a phenotype which fulfills the clinical criteria to establish the diagnosis of arrhythmogenic cardiomyopathy confirming the dysfunctional adhesion hypothesis. Now mechanistically, deregulation of integrin alpha V beta six and TGF beta signaling was identified as a central step in the process toward developing fibrosis. And then finally, a pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. So perhaps, new information leading to future therapeutic strategies to halt myocardial fibrosis in patients with arrhythmogenic cardiomyopathy.

Dr. Peder Myhre:

Oh wow. What an amazing issue this is, Greg, and we actually have even more in the mail bag. We have a Perspective piece by Dr. Prystowsky entitled “Rate versus Rhythm Control for Atrial Fibrillation, Has the Debate Been Settled?” And we have some Cardiology News by Bridget Kuehn entitled, “Fitness Rather than BMI Appears to be Better Predictor of Survival for Women with Heart Disease.” I'm sure Carolyn would love to read that one. And in this paper, Bridget Kuehn discusses a new study published in European Journal of Preventive Cardiology.

Dr. Greg Hundley:

Very nice, Peder. Well, I've got a couple other articles in the issue. First, Dr. Tonelli has a Primer entitled, “Increasing Societal Benefit from Cardiovascular Drugs.” And then Professor Januzzi has a Research Letter entitled, “Association Between Sacubitril/Valsartan Initiation in Mitral Regurgitation Severity and Heart Failure with Reduced Ejection Fraction: The PROVE HF Study.” Well, now let's get on to that feature discussion in this issue to discuss PCI versus CABG for multi vessel coronary artery disease.

Dr. Peder Myhre:

Let's go.

Dr. Greg Hundley:

Welcome listeners to this November 22nd feature discussion and we have with us today Dr. Jung-Min Ahn from Seoul, South Korea and our own associate editor, Dr. Manos Brilakis from Minneapolis, Minnesota. Welcome gentlemen. Jung-Min, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Jung-Min Ahn:

Thank you, Greg. So the everolimus-eluting stent Freedom trial, showed a higher mortality after PCI than after bypass surgery in multi vessel disease. However, these findings maybe delimited predictability in the contemporary practice because such trials use the first generation drug stent which may have higher rate of stent thrombosis. The Press trial is the first randomized trial using the second-generation drug eluting stent. The initial approach was published in New England Journal of Medicine five years ago. So they showed that the 4.6 years of follow the PCI with everolimus-eluting stents showed a significantly higher rate of prime endpoint deaths, MI, the target revascularization, but overall mortality, there was no significant difference. So the hypothesis that, in a long term follow, more than 10 years follow, so we want to see the mortality difference between the PCI with the second generation everolimus-eluting stent versus bypass surgery. So we designed this extended follow trial best studies.

Dr. Greg Hundley:

Very nice, Jung-Min. And can you describe for us the study design, and who was your study population, and how many subjects did you enroll?

Dr. Jung-Min Ahn:

Actually, this study is the extended follow original Press trial, enrolled 880 patients from mostly Korea, China, Malaysia, and Thailand. So the study population was Asian population with a symptomatic or symptomatic coronary artery disease with angiopathy confirming the multi vessel coronary artery disease population. One additional criteria is the patient with coronary artery disease should report PCI and bypass surgery decided by the attending physicians and surgeons.

Dr. Greg Hundley:

Thank you, Jung-Min. And so, can you describe for us your study results?

Dr. Jung-Min Ahn:

Yes. During the extended follow-up study we found that there is no significant difference between the PCI with everolimus-eluting stent and bypass surgery regarding prime endpoint deaths, MI, vascularization. In addition, more importantly, we reduced the compost endpoint of death, MI, stroke. There was no significant difference in addition regarding the mortality. Also, there is no significant difference during the long term follow.

Dr. Greg Hundley:

Really interesting results, Jung-Min. Did you notice any differences in men versus women or in younger versus older individuals?

Dr. Jung-Min Ahn:

In our sub-group analysis, there is no interaction according to the sub-groups except the diabetic sub-groups. In diabetics and long term outcomes, have interaction with the treatment assignment regarding the primary endpoint, prime endpoints, death, MI, target vascularization. Even though contrary to the Freedom trial, the overall mortality rate, there is no significant difference between the PCI versus the bypass surgery even in diabetic populations.

Dr. Greg Hundley:

Well thank you so much, Jung-Min. And now listeners, we're going to turn to our Associate Editor, our expert in the area of advanced percutaneous coronary artery interventions, Dr. Manos Brilakis from Minneapolis, Minnesota. Manos, you have many papers come across your desk. What attracted you to this particular paper and how do you put its results in the context of other studies that have been performed to compare multi vessel percutaneous coronary artery intervention versus coronary artery bypass grafting?

Dr. Manos Brilakis:

Yeah, thank you, Greg. And again, congratulations to Jung-Min for a great paper. And the reason we were very interested in this paper is because it is an area that is still debated clinically quite extensively. As Jung-Minh mentioned, there is the Syndex trial showing that there was higher mortality amongst the PCI group over long term, but that was done a long time ago with previous generation drug diluting stents, and the data, the contemporary data with recently the currently used DS, is much more limited. So I think the appeal for us, and I think frankly for the practicing interventionalist, is that this paper provides long term outcomes with contemporary drug eluting stents over a fairly large patient population, and it does so fairly well, but there are plus and minuses.

There was no difference in mortality, which continues to be debated. But this paper is fairly equivalent on this respect. And if we see the coupled myo curves, they also look very similar. And there was some differences in death in myocardial infarction to be taken into consideration. But all this information is important for deciding for each patient we treat right now, which is the best way to go in terms of coronary devascularization.

Dr. Greg Hundley:

Very nice. And so, let's circle back next to Jung-Min. What do you see as the next research study really to be performed in this sphere of investigation?

Dr. Jung-Min Ahn:

Thank you, Greg. So I'd like to talk about the future study, but I'd like to say something about the how to do PCI. So what is the difference between the Press trial and previous randomized trial? In the Pres trial, we used the intracoronary imaging in 72% of PCI population. This is a huge higher rate than what was used compared with the previous randomized trial. Only 10% or less than 10% PCI population used intracoronary imaging. So I think to get the comparable research to the bypass surgery, I think we have to optimize the PCR region. What is the best way shortcut to get optimizing PCR region? It could be intracoronary imaging guided PCI, could be one important way to get optimized PCR region. I think this is very important to take a message from the first trial.

Dr. Greg Hundley:

Well, Jung-Min, it sounds like from your description that the application of intracoronary imaging was very important in this study. Do you want to expand on that for our listeners? You know, what were maybe some subgroup analysis results of using intracoronary ultrasound? And then, how would you recommend to our listening audience that that particular technique be applied?

Dr. Jung-Min Ahn:

Thank you, Greg. So I mentioned that the Press trial used the intravascular ultrasound in 72% of PCI. So we analyzed the the PCI with I, without I. PCI with I showed a very comparable primary endpoint and overall mortality rate to the bypass surgery group. But PCI without I showed a significantly higher rate of primary endpoint and overall mortalities. So intravascular ultrasound guided PCI may improve the PCI outcomes and we can compare our clinical outcomes to the bypass surgery.

Dr. Greg Hundley:

Very nice. And Manos, do you have anything to add?

Dr. Manos Brilakis:

Yeah, I think the era of doing multiple huge mega trials may be tough to find these days. I think we may not have big trials comparing those two modalities, but I do agree with Junh Minh. I think the conclusion from this study as well as the previous studies is that you can choose which way to go. But if you're going to go with PCI for example, you do want to make sure that you do the best possible outcome so that you use intravascular imaging, you use physiology. We know from phase three, that use of intravascular imaging was very limited. So if you're going to go with PCI for a specific patient, the decision of course depends on the study's results and the previous studies and the patients' specific preferences. But if you're going to do PCI, you want to take your time to get the best possible result, make sure you can get as complete revascularization as possible because that will translate into better clinical outcomes as well.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank our main author today, Dr. Jung-Min Anh, and our own associate editor, Dr. Manos Brilakis, for bringing us this important study highlighting that in patients with multi vessel coronary artery disease, there were no significant differences between PCI and coronary artery bypass grafting in the incidence of major adverse cardiac events, the safety composite endpoint, and all cause mortality during an extended follow up period. Well, on behalf of Peder, Carolyn, and myself, we want to wish you a great week and we will catch you next week On the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. 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, please visit ahajournals.org.