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Circulation on the Run

Jul 29, 2019

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 cohosts. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             I'm Greg Hundley, Associate Editor of Circulation, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Greg, guess what? We are going to be talking later about non-inferiority trials. Now, you're going to go like, "Huh? What?," but then we see more and more non-inferiority cardiovascular trials. And do we really know the advantages and limitations of this type of trial design? Which is so important to understand, because we need to understand the factors that may impact our confidence and interpretation of these results. So, that's going to be a really important feature discussion, coming up right after our coffee chat. Greg, what are your papers?

Dr Greg Hundley:             Thanks Carolyn. Boy, I can't really wait to get to that feature discussion. That's something that we deal with all the time, and I look forward to that explanation and that discussion. I'm going to talk a little bit of basic science, with two papers right in a row.

                                                And the first one involves catecholaminergic polymorphic ventricular tachycardia through inhibition of calcium/calmodulin-dependent kinase II. The lead author is Dr Vassilios Bezzerides from Boston Children's Hospital.

                                                Carolyn, this paper focuses on treatment of catecholaminergic polymorphic ventricular tachycardia, an underlying diagnosis in at least 12% of pediatric patients who present with unheralded cardiac arrest. ICDs, as you know, are frequently implanted, but are problematic because of increased complication rates in pediatric patients, failure to convert ventricular arrhythmias, and the risk of fatal ICD-induced electrical storm. Modulating CaM Kinase II within the heart shows promise to treat this, but CaM Kinase II is essential in other tissues, most notably the brain.

Dr Carolyn Lam:                How interesting. So, what did the study show?

Dr Greg Hundley:             Well, the investigator used adeno-associated viral gene therapy, which is proven to be a safe and efficient vector for sustained gene transfer into many cell types to selectively inhibit CaM Kinase II in cardiomyocytes. They were able to express the specific CaM kinase II inhibitory peptide AIP in cardiomyocytes without significant extra cardiac expression, and an inhibition of CaM Kinase II effectively suppressed ventricular arrhythmias in a murine model of catecholaminergic polymorphic ventricular tachycardia after a single therapeutic dose. So thus, in animal models, delivery of a CaM Kinase inhibitory peptide by AAV represents a novel single dose gene therapy for catecholaminergic polymorphic ventricular tachycardia. How about that?

Dr Carolyn Lam:                Wow. You've got a second paper?

Dr Greg Hundley:             I sure do. So now we're going to jump into, again, looking at polymorphic VT from engineered human heart tissue. And this article is from Kevin Parker at Harvard University, "Modeling of Human Arrhythmias Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes has Focused on Single-Cell Phenotypes."

                                                With this said, it is important to realize that arrhythmias are emergent properties of cells assembled into tissues and the impact of inherited Arrhythmia mutations on tissue level properties of human heart tissue. And therefore, newer technologies are needed to develop more satisfactory therapeutic interventions. Ones that encompass all of the tissue, not just single cells.

Dr Carolyn Lam:                Interesting. So, what did this particular study do?

Dr Greg Hundley:             So, Carolyn, in this study, the investigators report on an optogenetically-based human-engineered tissue model of catecholaminergic polymorphic VT, which as we have discussed in the previous article is promoted by mutation of the cardiac ryanodine channel 2, which is promoted by mutation of cardiac ryanodine channel and triggered by exercise. They developed a human IPSC cardiomyocyte-based platform to study the tissue level properties and investigated pathogenic mechanisms in polymorphic VT by combining this novel platform with genome editing. The authors found that engineered heart tissue, fabricated from human pluripotent stem cell derived cardiomyocytes, effectively modeled catecholaminergic polymorphic VT caused by dominant mutations in the cardiac ryanodine receptor, including induction of arrhythmias by conditions that stimulate exercise. Using selective pharmacology and genome editing, the authors identified activation of calcium/calmodulin-dependent kinase II, or CaM Kinase II, and CaM Kinase II mediated phosphorylation of ryanodine at Serine 2814 as critical events that are required to unmask the latent arrhythmic potential of catecholaminergic polymorphic VT, causing ryanodine mutations, highlighting a molecular pathway that links beta adrenergic stimulation to arrhythmogenesis in this disease.

Dr Carolyn Lam:                Wow Greg! So, two very interesting and important linked genetic papers. Well, we're going to switch tracks a little bit and talk about, well, my favorite topic: heart failure with preserved ejection fraction and the whole complex issue of the diagnosis of this syndrome. Now we know that the diagnosis is kind of complex and there is currently no consensus but several proposed definitions. So how do the clinical and hemodynamic profile of patients vary across the different definitions of HFpEF?

                                                So, this question was answered by Dr Jennifer Ho from Massachusetts General Hospital and her colleagues, who examined consecutive patients with chronic exertional dyspnea and an ejection fraction above 50% who are referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. They applied societal and clinical trial HFpEF definitions and compared the clinical profiles, exercise responses, and cardiovascular outcomes by these different definitions. So, of 461 patients, 416 met the ACC/AHA definition, 205 met the ESC definition, and 55 met the HFSA criteria for HFpEF.

                                                The clinical profiles and exercise capacity varied vastly across the definitions, with peak oxygen uptake averaging 16.2 for those with the ACC/AHA definition and down to 12.7 in those satisfying the HFSA definition.

Dr Greg Hundley:             Wow. What a difference from these societies.

Dr Carolyn Lam:                Mm-hmm (affirmative).

Dr Greg Hundley:             So Caroline, it sounds like they looked at all comers with exertional dyspnea. Now how about those that had hemodynamic evidence of heart failure with preserved ejection fraction?

Dr Carolyn Lam:                Yeah, good question Greg. So, you caught me telling you that all these patients had hemodynamic cats as well, and a total of 243 had hemodynamic evidence of HFpEF, which was defined as an abnormal rest or exercise feeling pressure. Of these, 222 met the ACC/AHA criteria, 161 met the ESC criteria, and only 41 met the HFSA criteria. Over a mean follow-up of 3.8 years, the incidents of cardiovascular outcomes range from 75 for the ACC/AHA criteria to 298 events per thousand-person years for the HFSA criteria.

                                                The application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. So in summary, the authors demonstrated significant diversity in the number of patients meeting HFpEF criteria. And using different HFpEF classifications variably enriched for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure really highlighted the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF sub-grouping to test therapeutic interventions. Now, these are all discussed in an important accompanying editorial by Michele Senni, Sergio Caravita, and Walter Paulus.

Dr Greg Hundley:             Wow Carolyn. It appears, depending upon the definition, we could really classify patients drastically differently.

Dr Carolyn Lam:                Yeah, an important paper indeed. And again, I would strongly encourage everyone to read that editorial as well. For my second pick, we're going to switch to CPR in children.

                                                So these authors, now led by Dr Rohan Khera from UT Southwestern, examined the prevalence and predictors of survival of children who progress from bradycardia to pulselessness in in-hospital cardiac arrest despite cardiopulmonary resuscitation. So they looked at almost 5,600 pediatric patients age more than 30 days to under 18 years of age, who received CPR at hospitals participating in the Get With The Guidelines - Resuscitation during 2000 to 2016 each CPR event was classified as bradycardia with pulse, bradycardia with subsequent pulselessness, and initial pulseless cardiac arrest. And the authors assessed for risk adjusted rates of survival to hospital discharge.

Dr Greg Hundley:             So Carolyn, what did they find? This is really interesting.

Dr Carolyn Lam:                Well, among hospitalized children in whom CPR was initiated, half had bradycardia with poor perfusion at the initiation of chest compressions and nearly one third of these progressed to pulseless in-hospital cardiac arrest despite CPR. Survival was significantly lower for children who progressed to pulselessness despite CPR compared to those who were initially pulseless. So, these findings suggest that pediatric patients who lose their pulse despite CPR are at particularly high risk and require a renewed focus on post resuscitation care.

Dr Greg Hundley:             Very interesting, Carolyn.

Dr Carolyn Lam:                Well, that wraps it up for our discussion. Let's go onto the featured discussion. Shall we, Greg?

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                Non-inferiority cardiovascular trials are increasingly being published and in the highest impact journals. Yet how much do we really know about these designs of the trial, of the non-inferiority trials? Well, I have to admit not much in my point of view, and I was so pleased to see our feature discussion paper really published in this week's journal, which really digs deep into non-inferiority trials and talks about time trends and perhaps some lessons that we should all bear in mind when we look at these. I'm so pleased to have the first author, Dr Behnood Bikdeli, to tell us about the study. And he is from Columbia University Medical Center, New York Presbyterian Hospital, Yale Center of Outcomes, Research and Evaluation Core, as well as the Cardiovascular Research Foundation in New York. We also have Dr Naveed Sattar, associate editor from the University of Glasgow. Behnood, could you tell us, so what made you look at this question and what did you find?

Dr Behnood Bikdeli:        For a while we've been very interested in profiling the cardiovascular trials, trying to understand a little better, what are the specific characteristics of the major child that we rely upon for research but also for clinical practice? Years ago, we did some studies for surrogate outcome trials and this, let's just say subsequent piece, where we tried to look into a randomized cardiovascular trial that use a non-inferiority design. We had a series of features in terms of quality metrics and methodological metrics that we wanted to look into. The over eight almost 27-year period, we identified 111 of these trials. Reassuringly, most of these trials inherited several important quality and methodological metrics that we were looking into. However, we also saw a significant room for improvement. There were quite a few quality or methodological metrics that some of these trials were not adhering to and we think it's important because ultimately for the design reporting and last reading of these trials, knowing these pluses and minuses would help inform people.

Dr Carolyn Lam:                That's great, Behnood. Now for those of us listening who don't think about this every day, could you give us some examples of the top errors perhaps to look out for?

Dr Behnood Bikdeli:        For example, in the typical superiority trials, when we want to test an intervention a versus intervention B, all that matters is we do a very good and adequately sized trial and rest of it is up to the study and how it goes to see whether or not something panned out. There was a significant difference between the new intervention versus the older ones, but in non-inferiority trials we have something called the non-inferiority margin and that's very highly relevant when it comes to the outcome that you're assessing when it comes to the ultimate results of the trial.

                                                If the investigators choose a very lenient y non-inferiority margin, they may end up calling an intervention non-inferior. They may give it a pass. While in reality the intervention has quite a lot of a risk or harmful profile compared with standard of care. But in the other side, as a clinical example, we have several interventional tools at hand, like transcatheter aortic valve replacement. Most of the indications where it's currently used came from large bell designed non-inferiority trials. Where they showed that it was almost as good as surgery, in some cases better, but also it had a lot of ancillary advantages.

Dr Carolyn Lam:                Thanks, Behnood. And you know here, I just want to call out to the readers. You have to look at this paper. Look at the tables and figures which are really so helpful. And Naveed, can I bring you in on this now? I mean, I just love this paper. It's such an important topic and I've never seen it addressed like this before. Could you tell us a little bit about what the editors discussed when we looked at this?

Dr Naveed Sattar:            I've been involved in a few non-inferiority trials and some of the factors that many of us discuss and some of course associated, sort of our clinical trials, and I've been involved normally in superiority trials, but increasingly we have cut our teeth in non-inferiority trials. So, some of the points that the paper picks up resonated well with us in terms of, one of the examples was Behnood and his team found that around about 40% of trials didn't even justify what their non-inferiority margin was. And that's something I've actually had detailed discussions involved in various trials with. And that's a really important point, but it isn't a, you have to be able to justify why you choose particular margin and what that margin would mean to the community. Otherwise you potentially could just pick something out there which really doesn't allow you to make a really strong non-inferiority claim. And I think that's one of the factors that you found, Behnood. Is that correct?

Behnood Bikdeli:              Absolutely. And that's a great point. Thank you. To us, there were two things about it. One was whether or not they provided any detailed justification for it exactly as you said, not that they're just picking up something because that's the sample size that they could achieve or that's the number that they felt comfortable with. But also the second piece of it, a respective of how they calculated or came up to the number, their readers have a right to know how this was calculated or were this came from, so it's the reporting part of it. Sometimes they reported both in the published paper and a study protocol or a design paper. Sometimes it was only in one of them. Sometimes as you mentioned, it was not mentioned in either, which puts the reader in a very difficult situation.

                                                So we think, and these were the best of the best trials in the highest impact journals. Probably if we look high and low elsewhere it's going to be even more challenging. So, we think there's a lot of room for improvement for the readers to expect cleaner, more comprehensive papers to come, but also for the trialist to report them with more clarity.

Dr Naveed Sattar:            And going forward, issue a nice figure that shows that the trend is that we are going to see more of these trials probably because you've got lots of better treatments now. So, you know it's getting harder, in the sense, in many areas of cardiovascular medicine to show superiority. So, there is a need for more trials which actually show benefits beyond just perhaps the main outcome in ways that you've explained in the particular paper.

                                                Do you think the FDA does enough in this particular area in terms of this helping investigators decide what the non-inferiority margins are? Or is that something in terms of the quality of the trials that needs a bit more investigation? I think your papers partly are pushed to say, "Actually we need to do these better. We need to justify them better. We need to look at them better." Because actually they do have a greater influence going forward.

Dr Behnood Bikdeli:        First, I cannot agree more. We are going to see a lot more of non-inferiority trials sort of, maybe because we have reached a ceiling effect when traditional intervention for superiority, but there's a lot of room to find interventions that are at least as safe or as good but have a lot of side advantages and ancillary benefits that's happened with some of the anticoagulants among other therapies available.

                                                In terms of the regulatory aspects, one of the things we were fortunate about was within our team, we had people with expertise on the trialist side while communicating with the regulatory bodies and also from people who were consulting to the FDA for assessment of non-inferiority trials. So, we were fortunate to look into several of the methodological or quality metrics that were being thought of and we consulted with the in-source guidelines and FDA guidelines. That said, I completely agree that, for example, the suggestions that you provided in one of the tables could hopefully help shape some of these trials in a more rigorous way. Or at least a reporting, which is also an important piece, would be more transparent ultimately for the readership.

Dr Naveed Sattar:            Absolutely. And transparency is really pivotal so that the readers completely understand what was done, what was predefined, and what was found so that they can make a proper judgment. And probably the final question I have in terms of, you make a good point that actually if the trials are not done well and there's a bit of slippage either in terms of loss of data or methodological issues, that then really pushes a trial towards a "no", in a sense you get a false reassurance of non-inferiority, but partly because the methodology wasn't robust enough. And it's really very critical for these trials, perhaps at least as critical as they are in superiority trials, but perhaps even more so. Is that a fair judgment?

Dr Behnood Bikdeli:        No, no, no. You're absolutely right. That's another very important point in the typical superiority trial, if any bias drives the results toward no difference. Investigators are naturally guarding against that because it's going to be very problematic in non-inferiority trials. Depending on the effect measure that they choose, it could actually falsely favor the intervention of interest because it might show a false assessment of non-inferiority, and there are ways to work around it. There are ways to correct for it, such as choosing both absolute and relative effect measures, which practically addresses this concern. Again, gets back to the importance of appropriate design and appropriate transparency to report the results in a robust way, both intentions to treat and has treated or per protocol, both relative effect measures and absolute effect measures.

Dr Naveed Sattar:            My sense of and getting back to you, but I think this will be a really seminal paper for the community to look at and really help us as a community to improve our conduct of such trials in the future because there will be more of these coming forward.

Dr Carolyn Lam:                And I couldn't have said that better, Naveed. I think the take home message is right there. Pick it up, have a look and especially have a look at those tables and figures. It's really going to help you read many, many journals.

                                                Thank you so much, Naveed and Behnood. Thank you audience for joining us on Circulation on the Run. Talk to you next week.

                                                This program is copyright American Heart Association 2019.