Dec 7, 2020
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 Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam :
Greg, today's feature paper is a research letter, but, oh my gosh, it is so interesting. It's about surgical explantation of transcatheter aortic bioprosthesis. TAVRs we know is on the rise and so is the rise of surgical explantation cases and we really need to understand it better. Hang on, we're coming to that, but maybe, let's start with some other papers in the issue first, shall we? Let me go first, you go grab your coffee and listen because we're going to talk about the efficacy of ertugliflozin on heart failure related events in patients with type II diabetes and established atherosclerotic cardiovascular disease in the results of the VERTIS CV trial.
Dr. Greg Hundley :
Carolyn, tell us a little bit about the VERTIS CV trial.
Dr. Carolyn Lam :
Sure. The primary results of the VERTIS CV trial have already been published. This cardiovascular safety trial was actually performed to satisfy the 2008 guidance from regulatory agencies for new antihyperglycemic agents. It found that patients with type II diabetes and atherosclerotic cardiovascular disease randomized to ertugliflozin achieved the primary objective of non-inferiority to placebo in time to first major adverse cardiovascular event or MACE, a composite endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke. The first secondary outcome in the hierarchal testing sequence was superiority for the time to composite of cardiovascular death or heart failure hospitalization, which was not met and therefore formal hypothesis testing ended with this endpoint. Now in today's paper, the authors led by Dr. Cosentino from Karolinska Institute and Karolinska University Hospital in Stockholm, Sweden, present the results from pre-specified analyses of the effect of ertugliflozin versus placebo on a series of heart failure related outcomes from this VERTIS CV trial.
Dr. Greg Hundley :
Ah, Carolyn. Tell us what were the results of this new study.
Dr. Carolyn Lam :
Of more than 8,200 randomized patients, almost 24% had a history of heart failure and almost 61% had a pre-trial ejection fraction available, including 959 patients with an injection fraction less than or equal to 45%. While ertugliflozin did not significantly reduce first heart failure hospitalization or cardiovascular death, it did reduce first and total hospitalization for heart failure events with a relative risk for first heart failure events being similarly beneficial number one, in those with versus without a history of heart failure and number two, in those with a history of heart failure with reduced ejection fraction or preserved ejection fraction. However, the risk reduction tended to be greater for those with an ejection fraction less than or equal to 45%. Although, the test for interaction by injection fraction was not significant. The effect of ertugliflozin on risk for first heart failure hospitalization was consistent across most baseline subgroups with a greater effect in three populations, including those with impaired kidney function and those taking diuretics. Now, this is discussed an editorial by Doctors Faiez Zannad and Martin Cowie. You must pick it up and read it.
Dr. Greg Hundley :
That's great, Carolyn. What a fantastic another piece of information on the SGLT2 inhibitors.
Dr. Greg Hundley :
Well, my first paper comes to us from Dr. Peter Liu from the University of Ottawa Heart Institute and his colleagues. Carolyn, this article focuses on cardiac hypertrophy, which as you know, is a key biological response to injurious stresses such as pressure overload. Also as you know, when cardiac hypertrophy is excessive, it can lead to heart failure. Innate immune activation by danger signals through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain-containing protein 1, or NOD1 and its adaptor receptor interacting protein, RIP2, may play a major role in cardiac remodeling and progression to heart failure. These authors hypothesized that NOD1 and RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone.
Dr. Carolyn Lam :
I like that, NOD1 and RIP2. What did they find?
Dr. Greg Hundley :
These authors found that innate immune NOD1/RIP2 signaling was a major contributor to cardiac remodeling following stress. This process was critically joined by and regulated through the mitochondrial danger signal protein adapter MAVS. The authors found that this novel complex coordinates remodeling, inflammatory response and mitochondrial energy metabolism in stressed cardiomyocytes, thus NOD1/RIP2 MAVS signaling complex may represent an attractive new therapeutic approach toward modulating LV hypertrophy mediated heart failure.
Dr. Carolyn Lam :
Very nice, Greg. Now in the next paper, do you remember the VOYAGER PAD trial? Well, it was the trial that demonstrated superiority of rivaroxaban plus aspirin versus aspirin alone to reduce major cardiac and ischemic limb events following lower extremity revascularization. Now clopidogrel is commonly used as a short term adjunct to aspirin after endovascular revascularization. However, does clopidogrel modify the efficacy and safety of rivaroxaban in this setting? Well, that's the question that today's paper is addressing and it is led by corresponding author, Dr. Hiatt from University of Colorado School of Medicine.
Dr. Greg Hundley :
What did they find, Carolyn?
Dr. Carolyn Lam :
Well in the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia, regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use as well, but with a trend for more ISTH major bleeding with clopidogrel use more than 30 days than a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization, regardless of concomitant clopidogrel with a short course of less than 30 days associated with less bleeding.
Dr. Greg Hundley :
Very nice, Carolyn. Well, my next paper comes to us from Dr. Hinson from the Jackson Laboratory for Genomic Medicine. Carolyn this paper focuses on a particularly challenging heart failure associated sarcomere gene, cardiac troponin T, that is encoded by TNNT2. Remember Carolyn, this is a thin filament protein that functions in the tripartite troponin complex, where calcium binds and triggers twitch force. Relative to other sarcomere genes, pathogenic TNNT2 variants are associated with poor prognosis as they carry an increased risk of sudden cardiac death that is disproportional to myocardial remodeling. The investigators used human pluripotent stem cell derived cardiomyocytes in cardiac microtissue and single cell assays and functionally interrogated 51 TNNT2 variants, including 30 pathogenic likely pathogenic variants and 21 variants of unknown significance called VUSs. They utilized RNA sequencing to determine the transcriptomic consequences of pathogenic TNNT2 variants.
Dr. Carolyn Lam :
Wow. And so what were those consequences, Greg?
Dr. Greg Hundley :
They found that hypertrophic cardiomyopathy associated TNNT2 variants increased cardiac microtissue contraction while dilated cardiomyopathy associated variants caused decreased contraction. Both of which parallel changes in myofilament calcium affinity. Transcriptomic changes, including NPPB levels, directly correlated with sarcomere function and could be utilized to predict TNNT2 variant pathogenicity. In summary Carolyn, this research found that number one, inheritance of pathogenic TNNT2 variance is a leading cause of cardiomyopathy and number two, the majority of TNNT2 variants identified in the human population are classified as those VUSs or variants of unknown significance, which limits their clinical utility in genetic testing. As such, reclassification of TNNT2 variants would improve cardiomyopathy risk determination and treatment responses for individuals harboring these variants.
Dr. Carolyn Lam :
Nice. Thank you, Greg. Well, in this next paper, I think the title summarizes it all: “Is There a Sex Gap in Surviving an Acute Coronary Syndrome or Subsequent Development of Heart Failure?” Well, Dr. Justin Ezekowitz from Vigor Center, University of Alberta in Canada and his colleagues used a large population based cohort of more than 45,000 patients with MI between April 2002 and March 2016, to examine the incidence and geographic findings, treatment and clinical outcomes of patients with a first time and MI. To elucidate the difference between sexes, a series of multi-variable models were created to explore all MI and non-ST elevation MI versus ST elevation MI over time.
Dr. Greg Hundley :
What did they find Carolyn?
Dr. Carolyn Lam :
Well, some attenuation of differences in clinical outcomes over time had occurred. Women maintained a higher risk than men of dying or developing heart failure in the subsequent five years post both STEMI or non-STEMI, even after accounting for differences in angiographic findings, revascularization and other confounders.
Dr. Greg Hundley :
Well, Carolyn, how about we get to some of the other articles in the issue. And I've got a really nice Research Letter from Professor Damien Bonnet entitled, “Addition of Corticosteroids to Immune Globulins is Associated with Recovery of Cardiac Function in Multi-inflammatory Syndrome in Children.” There's also a Research Letter from Professor Peter van der Meer entitled, “Human Pluripotent Stem Cell Derived Cardiomyocytes of Peripartum Cardiomyopathy Patients Reveal at Aberrant Regulation in Lipid Metabolism.” And Carolyn, finally I have an ECG Challenge entitled, “Wide QRS Complex Tachycardia in a Young Pregnant Woman, is it SVT or VT?” The age old question from Dr. Gunaseelan.
Dr. Carolyn Lam :
Nice. Well, there's also an exchange of letters between Drs. Ross and Loupy regarding the article, “Identification and Characterization of Trajectories of Cardiac Allograft Vasculopathy after Heart Transplantation: a Population Based Study,” and a beautiful Perspective piece by Dr. Verma entitled, “Two Tales, One Story and that is talking about the EMPEROR-reduced and DAPA-HF trials.” A beautiful summary there. Let's get on now though to that feature discussion. Shall we, Greg?
Dr. Greg Hundley :
You bet looking forward to it.
Dr. Carolyn Lam :
Transcatheter aortic valve replacement or TAVR has indeed become an established alternative to surgical aortic valve replacement for patients with severe aortic stenosis. Now, while the TAVR usage has increased, so has surgical TAVR valve explantation. However, that's not been really well described its clinical impact or outcomes well until today's research letter in Circulation, which represents the largest series of TAVR explants from a national database. And I'm so pleased to have with us the first and corresponding author, Dr. Shinichi Fukuhara from University of Michigan to describe the study as well as our associate editor, Dr. Tim Gardner from University of Pennsylvania. Welcome, gentlemen. Shinichi, if you don't mind for non-interventionists and non-surgeons like myself, why would you need to explant TAVR in the first place? Maybe you could start with that and then tell us about your study.
Dr. Shinichi Fukuhara:
First of all, thank you so much for the kind invitation. It's a great honor to be with you and Dr. Gardener. That's a very good question and a very timely question actually. When we started implanting TAVR valves probably about nine years ago or so, that was when the TAVR valve was FDA approved, we were not thinking about second TAVR procedure after the initial TAVR valve fails. And then as time goes on, we started to recognizing, some patients' TAVR valves started failing and these failure patterns can be paravalvular leak, can be structural valve degeneration, can be endocarditis. Not all patients with a failing TAVR valve can be treated with a second TAVR valve procedure and the most common driving factor at least in my program at the University of Michigan is unsuitable anatomy for a second TAVR valve and the most common anatomy pattern is a risk of a coronary artery obstruction by the second TAVR valve. These are the common scenarios where patients need TAVR valve explantation scenarios.
Dr. Carolyn Lam :
Thank you so much for that as a background. And as you nicely set up in your paper, as we do more TAVR, obviously there are going to be more situations like this. Please tell us what you found.
Dr. Shinichi Fukuhara:
First of all, what we found from this project, first, surgical TAVR valve explant procedure is not as simple as people thought it would be. I remember back in 2014, 2015 when I was still a trainee, people were talking about, which is better TAVR SAVR TAVR or SAVR TAVR SAVR? However, based on what we are just starting to see, TAVR SAVR sequence may not be a good option for younger people based on the present study data. The fact that more than 50% of patients who require the major simultaneous procedures such as aortic repair and the mitral procedures is a something TAVR implanters in our community should be more aware.
Tim Gardner:
I think it's very important for Shinichi to tell us to emphasize the mortality rate that you saw with the SAVRs following TAVR because that's really, I think the sobering information here. This is not comparable to doing a redo aortic valve or redo SAVR. Just tell us about that, Shinichi.
Dr. Shinichi Fukuhara:
First of all, these STS database. We have a STS predicted risk of a mortality, which is available for patients undergoing isolated SAVR procedure. And then based on the even isolated the SAVR procedure, the OE ratio of observed to expected mortality ratio was actually higher than 1.5 for isolated SAVR procedure in patients requiring TAVR explant. More importantly, patients who are requiring TAVR explanted SAVR, as well as a concomitant cardiac procedure are demonstrating almost close to 20% mortality rate, which is to me very striking after we analyze that data set. And this is something our community, the TAVR implanters in our community should keep in mind.
Dr. Timothy Gardner:
Yeah. Obviously not only is the surgery, the removal of the TAVR device and replacement with a surgical valve, not only is that complex anatomically and technically, but the associated mortality seen in this series of patients that they reported is higher than expected and actually quite high in terms of absolute operative or hospital mortality. I take this important research letter as a sort of a warning message to all of us, in particular, the cardiology community, to realize that once a TAVR valve is placed, it is more difficult and riskier to remove that and replace it with a surgical aortic valve replacement, if for some reasons such as endocarditis or valve failure or whatever comes to play.
Dr. Timothy Gardner:
And obviously as Shinichi has already said, when you're looking at a younger patient, patient under 60 for example, who needs an aortic valve procedure, you need to keep in mind whether as he said earlier, it's might be safer to do a SAVR first. And then if there's another procedure required, that could be because of valve failure, a TAVR could be done rather than just assuming that the TAVR is going to be there and that it can be easily replaced or taken care of. At any rate, I think that's the very important point of this paper. And I think this is really the first report and not only by the way, does it show that this is happening, but in the most recent year of your report, Shinichi, how many SAVRs after TAVR were reported, number of cases?
Dr. Shinichi Fukuhara:
The 2018, the last year of this study period was actually the highest obviously and it was a close to 300 cases reported. And then the number of case is a steeply increasing as I demonstrated in the figure one in the paper.
Dr. Timothy Gardner:
That really emphasizes obviously TAVR volume is increasing. TAVR is now being placed in younger patients who have perhaps a greater chance of requiring a second procedure. And if it has to be explantation of the TAVR because of the complexity and the inability to use another TAVR to fix the valve, the technical challenges and the operative risks are much higher.
Dr. Timothy Gardner:
Well, I just think that this is a warning call that we have to be realistic about the secondary requirements for patients that have TAVR and we don't yet even have a much more than a 10 year experience with TAVRs and we're seeing an increasing number of patients just in the STS database who are having to come back for TAVR explant and it's a difficult, challenging procedure. One point that Shinichi made in his article is that this technical challenge of TAVR explant may be something patients requiring this procedure may need to be referred to surgeons and hospitals with high aortic surgery volume. This is not necessarily a procedure that a surgeon can get experienced with and comfortable with doing two or three a year. That's another bit of the message here.
Dr. Carolyn Lam :
Thanks, Tim. And Shinichi, what would be your take home message to the clinical community listening in?
Dr. Shinichi Fukuhara:
Thank you so much. Yeah, this is a little bit redundant statement, but I think that another important message from this paper is that these low risk younger patients choosing to have a TAVR procedure as the initial valve therapy should be informed of the future procedure risks of a TAVR explant which frequently requires more of device explanating and the possible unplanned concurrent procedures and for these reasons careful assessment of aortic root anatomy and the feasibility of a repeat TAVR procedure should be part of with the initial TAVR workup. If we decide to proceed with TAVR for younger patients and then therefore heart team approach remains extremely important in the TAVR practice, that's my take home message.
Dr. Timothy Gardner:
And I'd like to reinforce that. This is, as we know, the heart team concept has been so important in providing optimal care for patients with aortic valve disease and this is a reminder of part of the discussion that should be happening at the heart team level.
Dr. Carolyn Lam :
Thank you so much. Clear take home messages that you've got right here on Circulation on the Run.
Dr. Greg Hundley :
This program is copyright the American Heart Association, 2020.