Preview Mode Links will not work in preview mode

Circulation on the Run


Dec 30, 2020

New in 2021, we will feature 2 Feature Discussions every other week. For this week, we start with author Michael Gold and editorialist Sana Al-Khatib as they discuss the article "Primary Results from the Understanding Outcomes with the S-ICD in Primary Prevention Patients with Low Ejection Fraction (UNTOUCHED) Trial." Then, we switch to an important discussion about children and COVID-19 as author Israel Valverde and Associate Editor Gerald Greil discuss "Acute Cardiovascular Manifestations in 286 Children with Multisystem Inflammatory Syndrome Associated with COVID-19 Infection in Europe."

TRANSCRIPT BELOW:

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.

Greg Hundley:

And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we have two features in this issue.

Dr. Carolyn Lam:

I know.

Greg Hundley:

Yeah. And I've got the first one. It's going to be evaluating the acute cardiovascular manifestations in 286 children with multi-system inflammatory syndrome.

Dr. Carolyn Lam:

Wow. That is so important in the current pandemic. Well, the other is also so important. It's really, really critical results from the subcutaneous ICD trial called UNTOUCHED. I think that one might change clinical practice. So, do you want to tell us about other papers first?

Greg Hundley:

Yes. Carolyn, I'm going to grab my cup of coffee and we'll get started and my first paper comes from China. Professor Junbo Ge. So Carolyn PCSK9, mainly secreted by the liver and released into the blood elevates plasma load density lipoprotein cholesterol by degrading LDL receptors. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, as well as the underlying mechanisms still remain unclear.

Greg Hundley:

So this group detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin a2b beta-3 activation, alpha granule release, spreading and clot retraction. They also investigated the underlying mechanisms. Using myocardial infarct models, they explored the effects of PCSK9 on microvascular obstruction and infarct expansion, post myocardial infarction.

Dr. Carolyn Lam:

Oh, nice. And what did they find?

Greg Hundley:

Well, Carolyn, PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, as well as myocardial infarct expansion post MI by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors, or aspirin, abolished the enhancing effects of PCSK9 supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.

Dr. Carolyn Lam:

Wow. Very interesting. Indeed, the pleiotropic effects. Well guess what? My paper talks about the first non-LDL lowering treatment that has been shown to reduce CABG in a blinded randomized trial. Greg, can you guess what that treatment was? Well, here's a hint, here's a hint. It's the REDUCE-IT trial.

Greg Hundley:

Well, Carolyn, thanks for the hint. It must be icosapent ethyl.

Dr. Carolyn Lam:

Indeed, indeed. As a reminder, REDUCE-IT was a multicenter double-blind placebo controlled trial, which randomized statin treated patients with elevated triglycerides, controlled LDL and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl at four grams daily or placebo. The primary and secondary composite end points were significantly reduced. The current paper examined all coronary revascularizations, recurrent revascularizations and revascularization subtypes. First revascularizations were reduced by icosapent ethyl versus placebo with a hazard ratio of 0.66, which is a number needed to treat of only 24. Similar reductions were observed in total revascularizations and across elective, urgent and emergent revascularizations. Icosapent ethyl significantly reduced PCI and CABG with a hazard ratio of 0.61. So, icosapent ethyl reduce first and total coronary revascularization, including PCI and CABG in patients with elevated triglycerides and high cardiovascular risk despite well controlled LDL. Isn't that cool?

Greg Hundley:

Very nice Carolyn. Well, my next paper comes from Professor Kari Alitalo, from the University of Helsinki. So Carolyn recent discoveries have indicated that in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. The author set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B or VEGF-B in the heart and the effect of VEGF-B on recovery from myocardial infarction.

Dr. Carolyn Lam:

So what were their results?

Greg Hundley:

Well Carolyn, the myocardial VEGF-B trans-gene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in sub-endocardial myocardium in adult mice and structural and functional rescue of cardiac tissue after myocardial infarction. So VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue. Well, Carolyn that's all of the main articles. How about we turn to some of the other articles and letters in the issue?

Dr. Carolyn Lam:

Yeah. Why not? And Greg, let me start by talking about an exchange of letters between Dr. Wei and Dr. Fox on interpreting the net clinical benefit from rivaroxaban plus aspirin versus aspirin for chronic vascular disease. There's also an ECG challenge by Dr. Patel elusively entitled, A Rainy Day. Here's a hint, it's about hypothermia. In cardiology news by Bridget Kuhn. She talks about how the pandemic throws cardiovascular trials off course, there is an On My Mind paper by Dr. Most entitled, The Striking Similarities of Multi-system Inflammatory Syndrome in Children and a Myocarditis-like Syndrome in Adults: The overlapping manifestations of COVID-19. As a couple of Research Letters, one by Dr. Malhotra on Defining the Normal Spectrum of Electrocardiographic and Left Ventricular Adaptations in Mixed Race, Male, Adolescent Soccer Players, as well as by Dr. Qi on adherence to a healthy sleep pattern and incident heart failure, a prospective study of more than 400,000 UK Biobank participants.

Dr. Greg Hundley:

Very nice Carolyn. Well, I've got a primmer review of Cardiac Involvement in Multi-system Inflammatory Syndrome in Children with the corresponding author being Dr. Kevin Freedman. Well, how about we get off quickly to those next two feature discussions?

Dr. Carolyn Lam:

Yay! Let's go, Greg.

Dr. Greg Hundley:

Well, listeners, we are to the first of our double feature for the new year 2021. And with me is Israel Valverde from King's College in London and our own associate editor, Dr. Gerald Greil from UT Southwestern in Dallas. Welcome gentlemen. And as we get started Israel, could you tell us a little bit about the background that framed this study and the hypothesis that you wanted to address?

Dr. Israel Valverde:

Thank you. I mean, the main problem we had in Europe around April 2020, was that both the Center for Disease Control and Prevention in the U.S. simulated a clinical ALIT about a newly described immune disease and inflammatory syndrome in children associated with a COVID infection. And there were similarities with all the well-known syndromes, such as viral myocarditis, Kawasaki disease, Kawasaki shock syndrome, and toxic shock syndrome, that we were a bit of confused, because of the overlap in clinical presentation, because it was a true diagnostics challenge. So the hypothesis in this study is we wanted to describe the cardiovascular implications in this newly described sinus syndrome.

Dr. Greg Hundley:

Very nice. So tell us a little bit about your study design and what study population did you assemble to address this question?

Dr. Israel Valverde:

I think that was the most difficult thing in the study, because thanks to the Association For European Pediatric Cardiology, the APC, we coordinated a multicenter study involving all they would appear on centers that we were 55 centers from 17 countries all over Europe. And we were able to recruit 286 children with this new newly described syndrome and cardiovascular manifestations.

Dr. Greg Hundley:

And tell us, what did you find?

Dr. Israel Valverde:

I think we can summarize that in three main findings. First is that cardiac involvement is very common in children with multi-system inflammatory syndrome associated with coronavirus disease, 2019 infection. Second, that inflammatory markers were significantly raised in most children, particularly their C-reactive protein, ferritin, pro-calcitonin, N-terminal pro BNP natriuretic peptide, interleukin 6, and D-dimer level. And finally, that 65% of patient with MIS-C had evidence of previous infection with severe acute respiratory syndrome coronavirus too, either by PCR, immunoglobulin M or immunoglobulin G.

Dr. Greg Hundley:

Were there any particular aspects of your results that may have segregated to the boys versus the girls?

Dr. Israel Valverde:

Not really. We couldn't find any differences between boys and girls, because our study population was quite similar, but we couldn't find any differences between them. What we found is that there is a huge difference between children and adults.

Dr. Greg Hundley:

And what was the age range of these children?

Dr. Israel Valverde:

From a couple of weeks, until 18 years old.

Dr. Greg Hundley:

And no differences in the scope of the syndrome that they experienced in the younger children versus the-

Dr. Israel Valverde:

Initially we found two peaks. Similarly to the peaks of viral myocarditises, which is affecting more of the children below two years, and also adolescence.

Dr. Greg Hundley:

Well Gerald, multi-system inflammatory syndrome in children. How to results from this study compare with perhaps other inflammatory disease processes that have been observed in children, such as Kawasaki disease, et cetera.

Dr. Gerald Greil:

So we and Circulation were very lucky to get a bunch of submissions regarding a MIS-C and also have a radio article regarding this and I would like to point our readers towards that. I think the key issue is it's a new disease entity. The community is pretty clear about it, that other diseases like Kawasaki disease have similarities, but it's not the same thing. And we wanted to be very clear about this. Obviously, more things need to be investigated, but the key findings where Dr. Valverde pointed out in other study groups within the U.S. and within Europe, all point to the same direction, that is a new entity, we need to further investigate.

Dr. Greg Hundley:

How about the cardiovascular aspects, what differences in cardiovascular disease with this syndrome, again, relative to other perhaps inflammatory diseases that might affect the heart in children?

Dr. Gerald Greil:

As far as we know. And once again, when we're talking about a very preliminary data, is that the outcome in children having MIS-C usually good. Dr. Valverde pointed out in his study series of more of 286 children, there was only one death and recovery was pretty high rate. We have similar findings from U.S. groups, other findings from a group in Paris and Europe. So, I would like to point our readers to other summaries where it's pretty clear that it's a new disease entity. Overall, it's actually rare in children. So we want to make a pretty clear point that it's a rare disease, which at this point in time seems to have a good outcome.

Dr. Greg Hundley:

Well Israel, I'm going to come back to you. What do you see is the next study that should be performed perhaps in this general area of cardiovascular disease for children?

Dr. Israel Valverde:

So I think what we have learned is that the way to move forward is the collaboration between centers. So now that we have a large study multicenter group, our idea is continue describing the long-term outcomes of the study population, because most of them recovered, but a few of them keep, for example, coronary artery dilatation. So do they recovering when you have time until you have time, do they do the ejection fraction, the function of the heart go back to normality soon? Or do we have to wait? So I think that's the next step forward to probably the long-term outcome of the study population.

Dr. Greg Hundley:

Longitudinal follow-up. And Gerald, do you have anything to add to that?

Dr. Gerald Greil:

I would just like to reiterate what Israel said, that we need to focus on multicenter studies. I hope Circulation can be a platform to reunite different groups around the world. Because as I mentioned before, I think we have a new disease entity in front of us. We don't know the long-term outcomes. And in the interest of our children confronted with new disease, we need to be very, very careful to learn how we need to follow up these children and how we potentially need to treat them in the long-term.

Dr. Greg Hundley:

Well, listeners, this has been a fantastic discussion with Dr. Israel Valverde from King's College in London and our own Dr. Gerald Greil from UT Southwestern, revealing some aspects of this multi-system inflammatory syndrome that's associated with COVID-19 in children. And so, on behalf of Carolyn and myself, well, we've got to get to the next feature. So, I'm not going to let you go just yet. Well, listeners, we are in the double feature year 2021. In our second feature discussion today, we have Dr. Michael Gold from Medical University of South Carolina and our own associate editor, Dr. Sana Al-Khatib, who has written an editorial on this paper. And she is from Duke University. Welcome to you both. Michael, we'll start with you. Could you describe for us a little bit about the background related to this paper and what hypothesis did you want to address?

Dr. Michael Gold:

Well, thank you. And thank you for this opportunity. The implantable defibrillator is a fundamental aspect of the treatment and prevention of sudden cardiac death. It's been around for almost 40 years now and is commonly used in the system has evolved from being a surgical procedure, requiring a thoracotomy to a transvenous procedure in which leads could be placed into the heart. While it's very effective, the major limitation of this in many people's minds were, major limitations were both of complications associated with the transvenous lead. Those include infections and lead failures, as well as unnecessary or inappropriate shock to patients. And based on that, the subcutaneous ICD was developed as the latest iteration of this technology in which a lead is placed under the skin and tunneled up along the sternum, so that one could sense and shock the heart when necessary without being subjected to an intravascular lead.

Dr. Michael Gold:

And the device has been around for 10 years or so. It's proven to be effective, but primarily used in niche populations of younger patients, patients with poor vascular access and those considered at relatively low risk with few comorbidities, such as patients with Brugada syndrome or long QT syndrome or possibly hypertrophic cardiomyopathy. We felt it was important both to establish the role of the subcutaneous ICD in a more typical group of defibrillator patients, as well as with the multiple evolutions now of programming, as well as technology within the device of seeing if the more modern contemporary devices were as effective in these sicker populations, and also could reduce some of the issues seen earlier in terms of higher rates of inappropriate shock therapy.

Dr. Greg Hundley:

So Michael we're working with subcutaneous ICDs. What was your study population and how did you design this study to really test the efficacy of the subcutaneous ICDs relative to the more conventional transvenous lead systems in these high-risk patients?

Dr. Michael Gold:

So what we did was to first identify a population and the most common population price of the implantation in the United States have for sure, in many of the countries is primary prevention patients and low ejection fraction. So we restricted the study to patients with an ejection fraction less than 35% and primary prevention, meaning have never had an episode of sustained ventricular tachycardia or cardiac arrest. So starting with that population, this was a prospective large registry. The bandwidth was out there to do a very large randomized trial, which was just done, although not as in a sicker patient population that study called PRAETORIAN was going on simultaneously. And what we decided was to be aggressive if you will. And we defined our endpoints for the study by looking at identified studies previously with transvenous ICDs that have the most contemporary programming and the lowest risk of inappropriate shock.

Dr. Michael Gold:

So we used the MADEIT-RIT study, which most people probably would consider it to be the ultimate, if not one of the two contemporary studies for that. And we wanted to essentially compare head-to-head results with that, obviously without those specific patients, but using that as in some ways a historical control or benchmark. So, we set what we wanted to use as our performance goal based on the MADEIT-RNT study for inappropriate shocks, as well as looked at complication rates, using performance goals that have been well-established by the FDA. And we use an 18-month time window, because that's a time when most inappropriate shocks as well as most complications will show up with this device.

Dr. Greg Hundley:

So what did you find?

Dr. Michael Gold:

So, what we found was first that we accomplished the goal of having patients who were had much more comorbidities or sicker, if you will. A majority of patients of the over 1,000 patients in the study had ischemic heart disease. I mean, ejection fraction, it was down 26%. In perspective, the early studies of the S-ICD, I mean, ejection fractions are 40% higher, almost 90% of patients have heart failure rather than a third of patients in previous studies and the incidents of diabetes, kidney disease, hypertension and other things with two to three times higher than what would have been done or shown in any early registries of the S-ICD. So we're very pleased about that. Again, there were over 1,100 patients in this study. And what we showed was that at 18 months, the inappropriate shock rate for the whole population was only 4%, hopefully 2.7% annually, which is quite low compared to any other S-ICD study and was very favorably compared with the MADEIT-RIT study easily met the performance goal for that.

Dr. Michael Gold:

And if we looked at that subgroup of patients who had generation three of the most modern of the S-ICD devices that have a newer discrimination algorithm, that number even became lower than that. So again, very, very reassuring to see what we found there and for the generation three device, it was only 2.9% of patients in 18 months had any inappropriate shock for that. And if we then looked at the other aspects of it, the all shock rate for appropriate and inappropriate shock was only 10% of 18 months, which meant the performance goal for that as well. And what's important about the all shock rate is that it's nice to show that the device can defibrillate a patient in the lab when you're testing them. And this was successful in 98, 99% of the time, which is typical for transvenous or subcutaneous devices. But when we looked at spontaneous arrhythmic events, it was highly effective, 100% of VT storms, and all but one case of a VTVF episode was converted with defibrillator, that one case actually spontaneously converted, but was officially listed as a failure, because it didn't convert right away.

Dr. Michael Gold:

But no patients had a cardiac due to ventricular fibrillation that could not be successfully treated or ended up requiring external defibrillation. And finally, despite a much sicker population, again, if you will, we showed that at 18 months, the overall complication rate from the device was only about 7% in total, which again is very low compared to what we'd expect to see with other devices. And no patient developed a bloodborne infection or a true lead failure, which is one of the major complications that, and dreaded complications of transvenous devices.

Dr. Greg Hundley:

Well, Sana as our editorialist, what stood out to you as being really important findings in this study?

Dr. Sana Al-Khatib:

First of all, I want to start by congratulating Michael and his team on the completion of this important study. And I agree that this has been a really important addition to the armamentarium of studies related to subQ-ICDs. We have had registries in the past. In fact, Michael alluded to the publication of the PRAETORIAN trial, which was really the first trial to compare the S-ICD with the transvenous ICD in a randomized control trial design. However, despite the important contributions of the PRAETORIAN trial, there were several things that remain unaddressed or unanswered in terms of the rate of the end points, especially in appropriate shocks with the newer S-ICD models. So where we had an abundance of those in the UNTOUCHED study, and then really the important question of do the results of that trial, which was largely not done in the United States, apply to the average patient, seen in the United States.

Dr. Sana Al-Khatib:

And then could those results be extrapolated to sicker patients, because as Michael very nicely highlighted that those patients were not as sick as patients that we see in routine clinical practice. So from my perspective, those are the findings of the UNTOUCHED study are really important, because we now have confirmation that the S-ICD is actually effective and safe in a patient population representative of the average patient seen in clinical practice in the U.S. with a primary prevention indication for the ICD, no really sicker patients, good representation of women, black patients. So overall, I think this trial really gives me a reassurance that the subcutaneous ICD is safe and effective, that the rate of inappropriate shocks with the newer generation of ICDs is really low. That said, I just wanted to highlight a couple of points that I'm hoping to see more data on as we go forward.

Dr. Sana Al-Khatib:

The study was only 18 months long. It would be good really to have a longer studies. Again, the average age of patients enrolled in the trial was on the younger side in the 50s, and I would love really to see more data on the S-ICD in older patients. And also as Michael said that these results were obtained in patients who had a primary prevention indication for the ICD on the basis of systolic heart failure. Well, we have other patient populations. And especially with, for example, patients with hypertrophic cardiomyopathy, where the rate of inappropriate shocks might be higher, and it would be great to see even more data as we go forward on that patient population and other subgroups of patients that were not included or not well-represented in the trial, but overall a really important trial.

Dr. Greg Hundley:

Very nice Sana. And Michael, just swinging back to you, what do you think are some of the next studies that might be performed in this space?

Dr. Michael Gold:

No, I think that Sana made some nice points. I should point out that, in its, I think appropriate vision, the FDA require as long-term evaluation of devices and studies. So the S-ICD post-approval study, which I'm fortunate enough to be involved with as well, is a five-year followup study. We've already published a little bit on two and three-year data, but we will have five-year data on this device in a patient that is closer to the S-ICD than the early registries. It was not restricted to just low EF patients, but it was a U.S.-only study of over 1,500 patients. So, a larger study that has the typical distribution of patients that we see in a U.S. practice who would be eligible for the S-ICD, those without pacing indications and both primary and secondary prevention patients. So I think that will be very important.

Dr. Michael Gold:

Where the technology is going is largely, there will still be iterations of longer battery life, smaller devices and those things, but there's been a real push to be able to also provide pacing therapy without the need for intravenous leads. So there are several models and systems approaches being used, including adding a lead-less pacemaker that will communicate with a subcutaneous ICD or placing a lead under the sternum, still extra vascular with the capabilities of pacing. So I think the next sort of group of trials will likely be seeing on this device other than simply looking at other populations in a little more depth will be further expansion of the technology to allow for a greater use of a device for those patients who may require a pacing.

Dr. Greg Hundley:

Well listeners, we want to thank Dr. Michael Gold from Medical University of South Carolina and Dr. Sana Al-Khatib from Duke University, our editorialists for describing this study. And in regards to those, or in regards to subcutaneous ICDs, providing confirmation that these devices are both effective and safe, particularly in a U.S. population for primary prevention of sudden death and really a high-risk patient population with low ejection fraction. On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run. This program is copyright of the American Heart Association, 2021.