Jan 18, 2022
Please join author Mohamed Abdel-Wahab and Associate Editor Stefan James as they discuss the article "Comparison of a Pure Plug-Based Versus a Primary Suture-Based Vascular Closure Device Strategy for Transfemoral Transcatheter Aortic Valve Replacement: The CHOICE-CLOSURE Randomized Clinical Trial."
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 Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, a very interesting topic, looking at closure devices at the sites of access for patients that are undergoing TAVR procedures. But before we get to that, how about if we grab a cup of coffee and start with some of the other articles in the issue. Would you like to go first?
Dr. Carolyn Lam:
I would love to and I would like to describe not just one, but two articles from recent SGLT2 inhibitor trials. So, the first paper is an analysis of the DAPA-HF trial. Now we know that circulating high sensitivity, cardiac troponin T predominantly reflects myocardial injury. And higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction or HFrEF. But what about the prognostic significance of changes in high sensitivity troponin T over time and the effects of Dapagliflozin and on clinical outcomes in relation to baseline levels, as well as the effect of dapagliflozin on the high sensitivity troponin T levels? Well, this is what this study answers. It's a biomarker substudy of the DAPA-HF trial from Dr. Berg of the TIMI study group at Brigham women's hospital and colleagues.
Dr. Greg Hundley:
Wow. Carolyn, very interesting. So remind us about the DAPA heart failure trial. What was it about?
Dr. Carolyn Lam:
Ah, well, DAPA-HF was a randomized double blind placebo control trial of dapagliflozin in patients with symptomatic HFrEF defined by injection fraction 40% or less wherein dapagliflozin significantly reduced the primary endpoint of cardiovascular death or worsening heart failure events. And in today's biomarker substudy increases in high sensitivity, cardiac troponin T over a one year interval of time were highly predictive of subsequent risk of worsening heart failure and cardiovascular death. The effect of dapagliflozin on the primary endpoint was consistent irrespective of baseline troponin T concentration with no evidence of attenuated treatment benefit in those with very high troponin T concentrations.
Dr. Greg Hundley:
Very interesting Carolyn. Now you've got another study. Is this one on EMPA?
Dr. Carolyn Lam:
You are right. Thank you. The next paper is and analysis of the Emperor-Preserved trial. As a reminder, Emperor-preserved study the SGLT2 inhibitor empagliflozin in patients with HFpEF this time, which is a left ventricular ejection fraction above 40, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. The current paper evaluated the efficacy of empagliflozin on health related quality of life in patients with HFpEF and whether the clinical benefit observed with empagliflozin varied according to baseline health status.
Dr. Greg Hundley:
Very nice, super review Carolyn. So what were the results of this study?
Dr. Carolyn Lam:
In Emperor-Preserved, baseline health status and quality of life did not influence the magnitude of effect of empagliflozin on the risk of cardiovascular death or hospitalization for heart failure. Empagliflozin improved health status and quality of life as assessed by the Kansas city cardiomyopathy questionnaire across all domains and at all measured time points. Thus an effect that appeared early and was sustained for at least one year.
Dr. Greg Hundley:
Very nice. So two really informative papers on SGLT2 inhibitors. Well Carolyn, I'm going to turn the conversation to the world of preclinical science and talk about Titin. So Carolyn, titin truncation variants are the most common inheritable risk factor for dilated cardiomyopathy and their pathogenicity has been associated with structural localization. The A-band variants with overlapping myosin heavy chain binding domains appear more pathogenic than the I-band variants and the mechanisms for this are not well understood. So these investigators led by Dr. Hinson at the Jackson Laboratory for genomic medicine, performed a study demonstrating why A-Band variants are highly pathogenic for dilated cardiomyopathy and how they could reveal new insights into dilated cardiomyopathy pathogenesis. Titin functions and therapeutic targets were assessed.
Dr. Carolyn Lam:
Wow, interesting. So what did they enroll in? How did they do this? what did they find?
Dr. Greg Hundley:
Great Carolyn, so human Cardiomyocytes and cardiac micro tissue functional assays revealed that highly pathogenic A-Band Titin truncation mutations generate four shortened titin poisoned peptides and diminish full length, titin protein levels. While less pathogenic I-band titin mutations only diminish titin protein levels. And so Carolyn, the authors developed a one and done, genome editing therapeutic approach using CRISPR technology to repair the reading frame of Titin truncation mutations in cardiomyocytes. And therefore these genome editing therapeutics could correct the underlying genetic lesion responsible for dilated cardiomyopathy due to these Titin mutations.
Dr. Carolyn Lam:
Wow. Interesting. One and done genome editing. You learn something new every day with circulation. You've got another paper?
Dr. Greg Hundley:
Yes, Carolyn. Thank you. And so this paper comes to us from Dr. Beiyan Zhou From the Yukon health, school of medicine and again, from the world of preclinical science. So Carolyn, while several interventions can effectively lower lipid levels and people at risk for atherosclerotic cardiovascular disease, cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to this cardiovascular event risk. Now monocytes and macrophages play central roles in atherosclerosis, but previous work has yet to provide a detailed view of macrophage populations involved in increased atherosclerotic cardiovascular disease risk.
Dr. Carolyn Lam:
Huh? Okay. Well, I'm super excited to hear what these investigators did Greg.
Dr. Greg Hundley:
Right, Carolyn. Well these authors developed a novel computational program. They call AtheroSpectrum, which identified a specific gene expression profile associated with inflammatory macrophage foam cells. And additionally, a subset of 30 genes expressed in circulating monocytes jointly contributed to the prediction of symptomatic atherosclerotic vascular disease. So therefore Carolyn, in the future, perhaps incorporating this new pathogenic foaming gene set with known risk factors may significantly strengthen the power to predict atherosclerotic cardiovascular disease risk.
Dr. Carolyn Lam:
Wow. Super interesting and well summarized. Thank you, Greg. Well also in today's issue, there's a Perspective by Dr. Kirtane on “The Long-Awaited Revascularization Guidelines are Out. What's In Them?” A Research Letter by Dr. Laffin on rise in blood pressure observed among us adults during the COVID 19 pandemic.
Dr. Greg Hundley:
Very Nice Carolyn. Well in our Cardiovascular News Segment, there's a piece on metabolic risk factors and how they drive the burden of Ischemic heart disease. Well, what a great issue here and now, how about we get onto that feature discussion?
Dr. Carolyn Lam:
Very Cool. Closure devices after TAVR. Here we go.
Dr. Greg Hundley:
Well, listeners welcome today to our feature discussion and we have with us Dr. Mohamed Abdel Wahab from Leipzig Germany. And we are going to discuss some issues pertaining to transcatheter aortic valve replacement, in terms of access to the arteries in the lower extremity. Welcome Mohamed. And can you start with, what was some of the background that led you to perform your study and what was the hypothesis that you wanted to address?
Dr. Mohamed Abdel-Wahab:
Thank you, Greg. And thank you for having me here. So as you mentioned, there are several cardiovascular procedures that currently require large-bore arterial access. The most common of these procedures is transcatheter aortic valve replacement. But there are other procedures as well, like endovascular aortic repair, mechanical circulatory devices. All of these require large-bore arterial access and of course, closure afterwards. And what we were interested in looking at was whether different types of vascular access site closure devices or strategies behave differently in the setting. Particularly in the setting of transcatheter aortic valve replacement. The reason behind this is that for many years, we only had one technique, to percutaneously close arterial access sites after these procedures. And these were mainly based on suture based devices or suture based techniques. Very recently, alternative techniques based on collagen plugs have been introduced.
Dr. Mohamed Abdel-Wahab:
And we know these types of devices or closure techniques from usual coronary intervention procedures for smaller access sites or for smaller sheath size. But they have been developed a step further for these large-bore procedures. These newer devices, particularly what we call the MANTA device, which is based on the collagen plug has been shown in initial visibility studies and also in registry based analysis to be very safe and effective. It leads to a very rapid hemostasis. And data from observational studies have suggested that it may be even superior to the suture based techniques, largely based on what we call the ProGlide device or the [inaudible 00:10:56]. And this is actually what we were aiming to look at. To compare these two different strategies based on two different devices. The suture based, the classical suture based technique using two ProGlides compared to the newer plug based technique using the MANTA in a population treated with TAVR.
Dr. Greg Hundley:
Very nice. And describe for us, your study design. And then also maybe explain a little bit more about the study population. Who did you include in this study?
Dr. Mohamed Abdel-Wahab:
So the design was more or less, very inclusive. So we designed the trial to more or less represent real word population. More or less [inaudible 00:11:40] population receiving transcatheter aortic valve replacement. So we included patients, of course where the procedure is being thought to be indicated and feasible by a multidisciplinary heart team. And also where the heart team thought that the transfemoral access route, which is the main route for the majority of patients, is obtainable and use of a percutaneous closure device is also possible.
Dr. Mohamed Abdel-Wahab:
Of course we had some exclusions. For example, patients where the use of a surgical access technique was necessary. They couldn't be naturally included in the trial. Patient that already had complications related, for example, to previous coronary angiogram PCI at the access site, they couldn't be included. But we were more or less, very inclusive in this trial. The trial population reflects the patients that are currently being treated with TAVR, so more or less an elderly population. More or less equally split-by males and females, which is very particular, again to the TAVR population. So this is a little bit different than the population that receives PCI, where we usually have a predominantly male population. This is not the case here. So these are the broad lines. Also reflecting current practice, the population that has been included in the trial is more or less overall, an intermediate risk population, when you look at the surgical scores.
Dr. Greg Hundley:
Very nice. So this was multicenter and then also patients were randomized to each of the two therapies, I believe. And was that a one to one randomization?
Dr. Mohamed Abdel-Wahab:
Exactly. So it was a multicenter trial. Patients were randomized between these two techniques. We mentioned the ProGlide based and the MANTA based in 1:1 fashion. And steering committee of course was more or less dominated by interventional cardiologists. Of course, in the context of this particular trial setting, the trial was only performed in Germany and it was an investigative initiated trial, not sponsored by the industry.
Dr. Greg Hundley:
Very nice. And can you describe for us, Mohamed, your results?
Dr. Mohamed Abdel-Wahab:
Yes. We actually hypothesized based on the observational data we have, that we will have less vascular complications with the MANTA based technique or the collagen based technique. At the end of the day, what we observed is completely the opposite. So the primary endpoint of the trial, which was what we call major and minor vascular complications defined according to the standardized criteria provided by the valve academic research consortium. These events occurred significantly more common in patients that were randomized to the MANTA based technique, as opposed to the ProGlide based technique, which was statistically significant.
Dr. Greg Hundley:
And did you observe those results across both the men and the women? And also, were there any differences in the results related to participants' age?
Dr. Mohamed Abdel-Wahab:
Yeah. So there were no interactions with various subgroups, both the predefined ones, including age and sex, as you mentioned. But also we looked at some post hoc subgroups, including for example, whether this is being affected by the size of the access vessels or by the presence and location of calcification, for example. But there were no interactions in all subgroups we looked at, with one exception which was chronic renal insufficiency. But all other subgroups showed actually no significant interaction, favoring the suture based, ProGlide based technique in all subgroups.
Dr. Greg Hundley:
Very good. And so can you describe in terms of, for individuals performing TAVR procedures and obtaining access, how do we use the results of your study to inform how we might move forward with closure of the artery in the future?
Dr. Mohamed Abdel-Wahab:
I mean, the first thing I would like to stress is the importance of doing randomized trials in general. Because I think this is not the first time we see opposite results when we are comparing randomized evidence with the evidence from observation studies, with the known limitations of observational comparative analysis. The second thing I think is really reassuring that the suture based technique that we know and that we have been using for many years now is safe and appears to be even more effective than the newly developed plug based technique. So this is one important information I think from this trial. The third piece of information is that the recently developed plug based technique, although being inferior in the study, it still may have some advantages in selected patients. And this is what we probably need to look at in a little bit more details in the future.
Dr. Mohamed Abdel-Wahab:
For example, what we realized from the study is that it could be a good option as a bailout device. So in some cases where the suture based technique has failed in the study, the crossover to the MANTA device was successful in the majority of cases. And may lead or help avoid complex endovascular interventions and implanting for example, stents or covered stents or even doing surgery. So this is something that is a nice observation from the dataset we have, but of course needs validation in larger studies.
Dr. Greg Hundley:
Very nice. And so really you've answered, kind of one of our key questions is, your thoughts on the next study that you see needs to be performed really in this area of research?
Dr. Mohamed Abdel-Wahab:
Yeah, so I think there are several things. One thing is, again, to look at potential patient subgroups that may benefit from the plug based device from the beginning. So probably it's not something that we should be using as a default strategy based on the results of this trial. But there could be certain subgroups we need maybe to dig a little bit more into the details or subgroups, if you wish to say so. Look a little bit more granularly at some patient groups that could benefit. But as mentioned, I think that the bailout indication is a very interesting one and needs to be looked at.
Dr. Mohamed Abdel-Wahab:
Not only in the TAVR setting, but also in the setting of other procedures. Such as for example, the use of mechanical circulatory assist device or ECMOs, where it may be difficult to apply these sutures post hoc. So the sutures that we apply during a TAVR procedure and what we use in this trial, this is the so-called preclosure technique. So you apply the sutures after gaining access. Then you insert your large-bore sheaths through the procedure. And then the sutures are already there and you can close the access site, usually without problems. Which is difficult, if you obtain access, for example, with an ECMO or an Impella. And then after a couple of days, you need to close it. So the sutures are not yet in place. In this particular scenario, it may be beneficial to use a plug afterwards. Or as a bailout device as previously Mentioned.
Dr. Greg Hundley:
Very nice well listeners. We want to thank Dr. Mohamed Abdel Wahab from Leipzig Germany for bringing us this study indicating that among patients treated with transfemoral TAVR, this pure plug based vascular closure technique using the MANTA VCD was associated with a higher rate of access site or access related vascular complications. Well, on behalf of 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 AHA journals dot org.