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Circulation on the Run

Jun 22, 2020

Today’s episode discusses the paper “Randomized Comparison of the Polymer-Free Biolimus-Coated Biofreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial”


Dr Carolyn Lam and Dr Greg Hundley also discuss the following:

“Incidence, Microbiology, and Outcomes in Patients Hospitalized With Infective Endocarditis” by Shah et al.
“Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage” by Joutel et al.

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

Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn our feature article this week, we're going to dive into evaluating stent efficacy and looking at biodegradable stents and polymer free stents, and I can't wait to get to that feature.

But before we do that, how about we get to other articles in our journal today? Would you like to start?

Dr Carolyn Lam: You bet, Greg. So this paper describes temporal changes in the incidence, microbiology and outcomes of infective endocarditis and the impact of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis in Scotland.

Dr Anoop Shah from University Center for Cardiovascular Science at University of Edinburgh, and colleagues used a Scotland wide individual level linkage approach to identify all patients hospitalized with infective endocarditis from 1990 to 2014, and linked their records in national microbiology, prescribing and morbidity and mortality datasets.

Dr Greg Hundley: Interesting, Carolyn. So what did they find in this study?

Dr Carolyn Lam: The crude incidence rate of infective endocarditis hospitalizations increased from 1990 to 1995 but has remained relatively static thereafter with both short and long-term adjusted case fatality rates showing a steady decrease over the last 25 years. However, the incidence rate has doubled in the elderly.

Importantly, there was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines. The majority of patients with endocarditis in their cohort did not have positive blood cultures. However, in those that did have positive microbiology, staphylococcus and enterococcus conferred the highest risk for all-cause mortality.

Dr Greg Hundley: Ah, very interesting. More in the world of endocarditis. Well, Carolyn, my paper is also interesting and it involves both mouse and human experiments to identify the etiology of deep intercranial hemorrhagic stroke. Now I'm not going to quiz you this week because I think you're going to want to quiz me in anticipation of some of these exciting study results.

A little bit of background. First of all, the study comes from Dr Anne Joutel from INSERM and it has been thought that smooth muscle cell degeneration at the site of arterial wall rupture may be sufficient to cause hemorrhage. However, deep intracranial hemorrhages are rare in some aggressive small vessel diseases that are characterized by significant arterial smooth muscle cell degeneration.

Therefore, the authors hypothesized that a second cellular defect may be required for the occurrence of intercranial hemorrhage. So to address this hypothesis, the author studied a genetic model of spontaneous deep intercranial hemorrhage in mice, and analyzed cerebral retinal micro vessels, performing genetic rescue experiments, vascular reactivity analysis, and computational modeling.

And in the human experiments, they examined post-mortem brain tissues from patients that had sporadic deep intercranial hemorrhage.

Dr Carolyn Lam: Wow, that's a lot of work from mice to men. Well, let's start with the mice. So what did they find there, Greg?

Dr Greg Hundley: Right, Carolyn. So the authors identified in the normal cerebral retinal vasculature, a novel segment between arterials and capillaries herein called the transitional segment, and that is covered by neural cells distinct from smooth muscle cells and parasites.

In Col4a1 mutant mice, this transitional segment was hyper muscularized with a hyperplasia of neural cells expressing more contractile proteins, whereas the upstream arterial exhibited a loss of smooth muscle cells.

Moreover, the hyper muscularization of the retinal transitional zone increased its contractility in tone and raised the intravascular pressure in the upstream feeding arterial.

Dr Carolyn Lam: Wow, masterful explaining, Greg. Okay. What about in the humans?

Dr Greg Hundley: Well, the author similarly found that hyper muscularization of the transitional segment and focal arterial or smooth muscle cell loss in brain tissues from patients were observed in those with sporadic deep intercranial hemorrhage.

Dr Carolyn Lam: Okay, so put it together for us, Greg.

Dr Greg Hundley: Right. So the results suggest that hyper muscularization of this transitional segment is involved in the incurrence of intracranial hemorrhage in these studied mice, and this hyper muscularization in this zone raises the intravascular pressure in the upstream feeding arterial and promotes its rupture at the site of smooth muscle cell loss.

The human data corroborate these findings indicating that these two mutually reinforcing vascular defects may represent a general mechanism of deep intercranial hemorrhage. Really interesting results.

Dr Carolyn Lam: Not just interesting, but very, very nicely summarized. Thanks Greg.

Well, other very interesting papers in today's issue include a research letter by Dr Tiantian Li et al, entitled Associations Between Short Term Exposure to Fine Particulate Matter and Cardiovascular Disease Hospital Admissions After Index Myocardial Infarction. A case crossover study from Beijing, China.

There's also a white paper from Dr Milton Packer on the role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient over abundance. This beautiful white paper presents a mechanistic framework that may explain the findings of large scale randomized trials of SGLT-2 inhibitors and the close association of ketogenesis and erythrocytosis with the cardio protective and renal protective benefits of these drugs. Interesting.

There's also a series of papers on COVID-19, including an online white paper by Dr Franz Messerli on COVID-19 and renin-angiotensin blockers, current evidence and recommendations.

A perspective paper by Dr Michael Givertz on the challenges in heart transplantation in the era of COVID-19. Another online paper by Dr Harsimran Singh entitled New York City innocence lost, cardiology in the COVID-19 pandemic.

Dr Greg Hundley: Wow, Carolyn, this issue is just truly full of a lot of articles in addition to our original research.

So I have an exchange of letters to the editor between Richard Sutton and Dr Ben Levine regarding Dr Levine's previously published tilt table manuscript.

Next, Dr James Byrd from the University of Michigan offers a perspective on pausing clinical research during the COVID-19 pandemic.

Dr Comilla Sasson from the American Heart Association heads a very large group of authors to provide a very nice piece on guidance for life support during the COVID-19 pandemic.

Next, Professor Guilo Stefanini from Humanitas University has a research letter regarding ST elevation myocardial infarction in patients with COVID-19, both the clinical and the angiographic outcomes.

And then finally, another ECG challenge from Dr Adrian Baranchuk entitled an ominous ECG sign in critical care.

Well, Carolyn, what a great issue, and let's get on to that feature discussion to learn a little bit more about bio resorbable intercoronary stents.

Dr Carolyn Lam: Great. Let's go, Greg.

Dr Greg Hundley: Well, listeners, We're here for our feature discussion. And today we have Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, one of our own associate editors.

Lisette, could you tell us a little bit about the background for your study of intercoronary stenting and what was the hypothesis that you wanted to address?

Prof Lisette Jensen: The overall background or aim for this program is that we want to have a quality control of what we put into the patients, what stent we put in, and also we wanted to do as much research as possible, and we want to do it if it's possible on a low budget.

For the present study, the Sort Out IX, before we did the study, we knew that the Bio Freedom stent was doing very well with a short time of dual antiplatelet therapy in patients with high bleeding risk. At the same time, we knew that the Orsiro stent was doing very well in all common populations, we used it in Sort out VII also.

We wanted to see how the Bio Freedom stent, the one you could use with a short time of dual antiplatelet therapy, how it was compared to a gold standard stent. In this study, we did not shorten the treatment time with dual antiplatelet therapy, but we followed the guidelines with six months for patients with stable angina, and 12 months for patients with acute coronary syndrome.

Dr Greg Hundley: Can you just remind our listeners, what's the difference between the Bio Freedom stent and then Orsiro stent?

Prof Lisette Jensen: There's several differences. The strut thickness of the two stents differs. The Orsiro stent is an ultra-thin stent strut and the Bio Freedom stent is 120 microns. Also, the Bio Freedom stent is free of a polymer, compared to the Orsiro stent where the polymer is biodegradable and is degraded in one to two years.

And also the drug is sirolimus in the Orsiro stent and it is released within three months compared to the Bio Freedom stent where most of the drug biolimus is released within one month.

Dr Greg Hundley: So the Bio Freedom is a stainless-steel drug coated stent, and the Orsiro stent is a biodegradable stent. So can you tell us what was the study design, and then the study population?

Prof Lisette Jensen: It was a randomized trial and we enrolled 3,151 patients. They were randomized one to one, two to two stent groups, and we followed the patients. The primary endpoint was after one year, and this is what we're going to publish now in the journal, and we plan to do up to five years follow-up in the patients.

Dr Greg Hundley: And what outcomes were you looking for?

Prof Lisette Jensen: The primary endpoint was MACE, and that was a composite endpoint of cardiac deaths, target lesion revascularization, and myocardial infarction, not clearly related to any other segment that the index listed.

Dr Greg Hundley: So 3,151 patients, so a very large study. Can you tell us a little bit about your study outcomes?

Prof Lisette Jensen: The outcome was the primary end point after one year was, we saw MACE rate in the Bio Freedom treated patients was 5.0% compared to 3.7% in the Orsiro group. And the study was designed as a non-inferiority study, so with these numbers, Bio Freedom stent did not meet the criteria for non-inferiority.


Dr Greg Hundley: And were there any particular patient populations or subgroups where you saw differences in performance from one stent versus the other?

Prof Lisette Jensen: We looked into several predefined subgroups, which are also in the paper as figure three where we did a force plot, and in all the pre-specified subgroups, including indication for PCI, acute coronary syndrome or stable angina, young patients, old patients, diabetic, non-diabetic, gender, we did not see any significant difference.

Dr Greg Hundley: Well, Dharam, I'd like to switch over to you a little bit. Can you help us put this study in perspective to the other world's literature related to intercoronary stenting?

Dr Dharam Kumbhani: You know, one of the biggest advantages of the way they enroll patients is they tend to be a lot more inclusive than many of the other trials that are done. So typically isn't all common population.

So, now and again, I think it was an important trial because as she just outlined, it compares the Bio Freedom stent, which is a polymer free stent to a biodegradable stent. And this was really the first comparison of this Bio Freedom stent with a more contemporary stent that is used in clinical practice.

There have been a couple of other trials like the industry three and industry two trial which have compared it with bare metal stents. We know that this stent has a better performance than that, but when you compare it with, especially the thin struts or Orsiro, the latest in this class of DES, it is the thinnest strut, one of the thinnest strut stents that is in the market. The strut thickness, we know it really correlates quite well in stent restenosis.

I think this really helps move the field forward in terms of having data available for this comparison, and it suggests that perhaps in this kind of pragmatic design, that this Bio Freedom stent did not necessarily in the timeframe that they studied, meet the criteria for non-inferiority compared with the Orsiro stent.

So I think there's still valuable insight. The stent is not yet approved in the US. None of the Bio Freedom stents are available in the US. This is CE Mark, but not available in the US.

So I think this does add to the overall body of literature for this group of stents.

Dr Greg Hundley: I would like to ask you both, perhaps one at a time. Lisette, you first. What do you see is the next research study that needs to be performed in this field? Lisette.

Prof Lisette Jensen: Can I just give one more comment to what Dharam mentioned with the restenosis, because that was actually what we saw in the Sort Out IX. We had a higher rate of the target lesion revascularization rate in the Bio Freedom stent group, so the efficacy was less.

It could be because of the bigger stent struts, pushing us in a direction where we should use stents with thinner stent struts. And also we saw that the safety did not differ as we saw the equal number of stent thrombosis within one year.

I think what we should do next is maybe we should continue to work on the thin stent struts, and then also for the patients, the bleeding matters a lot. So it should be better to reduce the bleeding time to develop devices where we can reduce the treatment time for dual antiplatelet therapy.

Dr Greg Hundley: Very good. Dharam, your thoughts?

Dr Dharam Kumbhani: I would definitely agree. I think one of the most appealing aspects of this group of stents, because they don't have polymer, the ability to shorten the duration of antiplatelet therapy. And over the last couple of years, we've seen an incredible change in how we think about dual antiplatelet therapy and a number of trials have really challenged that dogma.

So I really think that a stent like this, I think it will be very interesting to study this in patients who are either high bleeding risk. This does perform better than bare metal stents, we know that. So conceivably we can get away with a much shorter duration of dual antiplatelet therapy, or just a lower duration of dual antiplatelet therapy in general.

So I would think that that would be one of the next areas of research in a randomized fashion for this group of stents.

Dr Greg Hundley: Well, listeners, we've had a wonderful conversation here with Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, related to some new evolutionary thoughts in intercoronary stenting.

For all our listeners out there on behalf of Carolyn and myself, we wish you a great week and look forward to speaking with you next week.

This program is copyright of the American Heart Association 2020.