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Circulation on the Run

Jun 3, 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 co-hosts. 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 for Circulation and Director of the Pauley Heart Center in Richmond, Virginia at VCU Health.

Dr Carolyn Lam:                So Greg, ever wondered if prophylactic use of ICDs would help prevent sudden cardiac death in dialysis patients? Well, guess what? We're going to be discussing it in the feature discussion of the ICD II trial coming right up. First, I hear you've got a very interesting probabilistic paper.

Dr Greg Hundley:             Yes. It's very sweet. This is from Renata Micha at Tusk University and it's examining the cost effectiveness of the US Food and Drug Administration added sugar labeling policy for improving diet and health. So Carolyn, in this study, investigators used a validated micro simulation US impact food policy model to estimate cardiovascular disease and type II diabetes mellitus cases averted, quality adjusted life years, policy costs, health care, informal care, and loss productivity in health related savings and cost effectiveness of two different policy scenarios.

                                                First, the implementation of the US Food and Drug Administration added to your labeling policy or just the sugar label. And second, further accounting for corresponding industry reformulation the sugar label plus reformulation. The models used nationally represented demographic and dietary intake data from the national health and nutrition examinations survey and diseased data from the centers for disease control and preventive wonder data base and policy affects in diet disease effects from meta-analysis and policy and health related costs from established sources. Probabilistic sensitivity analysis accounted for model parameter uncertainties and population heterogeneity.

Dr Carolyn Lam:                Sweet indeed, so tell us all about probabilistic analysis Greg.

Dr Greg Hundley:             Okay Carolyn, so between 2018 and then forecasting out into the future, so this is probabilistic, in the year 2037. The sugar label would prevent 354,400 cardiovascular disease cases, and 599,300 diabetes mellitus cases, gain 727,000 quality adjusted life years, and save 31 Billion dollars in net health care costs. Or 61.9 Billion dollars in societal costs incorporating reduce loss productivity and informal care costs and similar findings were accomplished for the sugar label plus reformulation scenario, both scenarios were estimated with greater than 80% probability to be cost saving by the year 2023.

                                                Thus, the results of this simulation exercises indicated that implementing the FDAs added sugar labeling policy could generate substantial health gains and cost savings for the US population particularly if the new label stimulates industry reformulation. The authors point out that the compliance date for updating the nutrition facts label including the added sugar perversion has been continuously delayed. And the authors believe, their findings highlight the need for timely implementation of this label so as to maximize health and economic gains.

                                                An excellent editorial was written by Elizabeth Magnuson at Saint Luke's Mid America Heart Institute revealing the strengths of this work and explains some of the variants that could occur in the results based on assumptions that were used in the authors micro simulation model.

Dr Carolyn Lam:                That is so interesting Greg, thanks. So from policy to guidelines and this time on cardiopulmonary resuscitation or CPR, now we know that an out of hospital cardiac arrest, chest compression only CPR has emerged as an alternative to the standard CPR where we use both chest compressions and rescue breathes. Since 2010, CPR guidelines recommend chest compression only CPR for both untrained bystanders and trained bystanders who are unwilling to preform rescue breaths.

                                                The current study really aimed to describe the changes in the rate and type of CPR perform before the arrival of emergency medical services doing three consecutive guideline periods with gradual adoption of compression only CPR and this was in Sweden. Now these were authors led by Dr Hollenberg from The Center of Resuscitation Science, Karolinska Institute in Stockholm, Sweden and colleagues and basically, they study all bystander witness out of hospital cardiac arrest reported in the Swedish register for CPR from 2000 to 2017. They found that there was a six fold higher proportion of patients receiving compression only CPR and a concomitant almost double rate of CPR before emergency medical services arrival, and these changes occurred over time. Any type of CPR was associated with doubled survival rates in comparison with cases not receiving CPR, and this association was observed in all time periods studied. They also found a small but significantly higher chance of survival after CPR with compression and ventilation in comparison with compression only CPR.

Dr Greg Hundley:             So Carolyn, does this mean we should go back to standard CPR?

Dr Carolyn Lam:                Well, remember these we observational findings, albeit really amazingly done and nationwide. But the findings really support continuous endorsement of the compression only CPR as an option and that's because its associated with higher CPR rates and overall survival of the no CPR skill. The authors ended up calling for randomized controlled trials, which are really needed to answer the question of whether or not CPR with compression and ventilation is superior to compression only CPR, especially in cases where bystanders have had the previous CPR training. Now, this is discussion in a wonderful editorial by Drs. Hsu and Neumar from University of Michigan Medical School.

Dr Greg Hundley:             Very nice, so you're going to tell us a little bit about troponin?

Dr Carolyn Lam:                Well, the question is "Is Plasma Troponin I measured by the high sensitivity assay associated with incident cardiovascular disease in the community?" Well, Dr Ballantyne from Baylor College of Medicine and colleagues decided to answer this question by looking at the ARIC Study participants age 54 to 74 years without base line cardiovascular disease and what they found was that elevated high sensitivity troponin I was strongly associated with increased global cardiovascular disease incidents in this general population, and this was independent of traditional risk factors. They also found differences between black and white individuals and between men and women.

Dr Greg Hundley:             What kind of differences?

Dr Carolyn Lam:                Well high sensitivity troponin I had a stronger association with incident global cardiovascular disease events in white compares to black individuals and a stronger association with incident coronary heart disease in women than in men. The authors also did a comparative association of high sensitivity troponin I vs. troponin T, they found that the high sensitivity troponins I and T show only moderate correlation with each other but were complementary rather than redundant in risk assessment for incident cardiovascular events in individuals without known clinical cardiovascular disease at base line. The bottom line is, adding biomarkers to traditional risk prediction models presents a potentially effective approach for future risk prediction algorithms for cardiovascular disease in the general community.

Dr Greg Hundley:             You know, think I might read that paper looking at that complimentary risk assessment. That sounds really interesting Carolyn. Well, I'm going to go back to the world of basic science and discuss a paper from Kun Wang discussing the long non encoding RNA regulation of cardiomyocyte proliferation and cardiac repair. Carolyn, post mitotic cardiomyocytes in the adult heart exit from the cell cycle and cease to proliferate, and that's the basis for their poor regenerative capacity and defective repair in response to say a myocardial infraction. Interestingly, the nonmammalian vertebrates such as our friend the zebra fish, their heart exhibits a robust capacity for regeneration. And it can efficiently regenerate its lost cardiac tissue throughout life due to this retain cardiomyocyte proliferation capability.

Dr Carolyn Lam:                Interesting indeed Greg about our friend the zebra fish. So what did the authors find?

Dr Greg Hundley:             Okay, in this study, Wang and associates investigated whether long non-encoding RNAs had a role in the regulation of cardiomyocyte proliferation and cardiac repair. Using bioinformatics and initial analysis, the identified a long coding RNA named Cardiomyocyte Proliferation Regulator or CPR that was comparatively higher in the adult heart as opposed to hearts in the fetal stage. The silencing of the Cardiomyocyte Proliferation Regulator or CPR significantly increased the cardiomyocyte proliferation in the postnatal in adult hearts, more over CPR deletion restored the heart function after myocardial injury which was evident from increased cardiomyocyte proliferation, improvement of myocardial function and reduce scar formation. Also, neonatal cardiomyocyte proliferation in cardiac regeneration where markedly suppressed in CPR overexpressing heart cells, therefore CPR acts as a negative regulator of cardiomyocyte proliferation and regeneration in fetal hearts.

                                                So, Carolyn the conclusion of this paper is that the inactivation or silencing of CPR accelerates cardiomyocyte proliferation along with significant restoration of cardiac structure and function after myocardial injury in adult hearts. And as such, further studies may investigate whether the therapeutic inter fashion of CPR could be a useful strategy to trigger the expansion of cardiomyocyte populations and myocardial repair.

Dr Carolyn Lam:                Nice Greg, so we've talked about CPR as in Cardiopulmonary Resuscitation to CPR as in Cardiomyocyte Proliferation Regulator, how about that? Well, that's as much as we go for now, let’s get to our feature discussion.

                                                Dialysis patients are known to have a high mortality rate, a large proportion of which have been attributed to sudden cardiac death and yet compared to patients with heart failure, these patients with dialysis have been either excluded or only nominally enrolled in all previous trials of implantable defibrillators or ICDs. Now that's why our feature paper this week is so important, and it is the Cardioverter-Defibrillator in the prevention of sudden cardiac death in dialysis patients that prospective randomized controlled ICD to trial. So pleased to have with us, the corresponding author Dr Wouter Jukema from Leiden University Medical Center as well as associate editor Dr Mark Link from UT South Western to discuss this very important paper. Wouter, congratulations, this is a very difficult, very important to do the study though, could you tell us a bit about what you did and what you found?

Dr J. Wouter Jukema:     Actually, you just referred to it as a very difficult study to perform and indeed it was. Many years ago, actually, twelve years ago, we noticed that now a lot of death in dialysis patients was attributed to sudden cardiac death, before we tried to make these type of patients better with all types of medications, but did not really work and suddenly the idea was, that came also from death certificates and death records that they have sudden cardiac death and we said we should monitor it and we should treat it in a prospective randomized study. We initiated the study after careful thoughts and we thought we would do it in 4-6 years but it took us 12. So it was quite an effort to set up this rightly and spread it around the Netherlands and activate a Nephrologist and a Cardiologist to take part in this prospective randomized controlled study in dialysis patients.

                                                Of course, you can easily imagine that you could have great benefit from this ICD devise, but you could also easily imagine that you would have complications of the implication of the device. So explaining that we should show it out, I think was the most important job we had to do and think that was a great effort, and it was not easy to do.

Dr Carolyn Lam:                And that in it of itself is very important observation.

Dr Mark Link:                     So you picked patients without doubts, which is great I mean this is a difficult study, but you also picked with an LDF greater than 35% and traditionally, ICDs are indicated for under 35%, can you give us a little explanation on why you chose the greater than 35% population?

Dr J. Wouter Jukema:     Yeah, I think this is perhaps the most important remark on the study, because when we designed the study we had to choose at that time we had guidelines in general that under 35% of injection fraction you were entitled to receive an ICD, however of course almost never dialysis patients were included so there was no formal recommendation on that not to include them or not to exclude them, but dialysis patients have a death rate at that time to sudden cardiac death, anyway regardless of the injection fraction and we thought okay, the patient population that is first at high risk of sudden cardiac deaths so any dialysis patients but also they are entitled to have a meaningful extension of the lives because the prognosis of patients that are on dialysis with an injection fraction under 35% is in general so poor that it would be unfair to start there and most of the Nephrologists also would not allow it anyway, these patients are at the end of life and if you extended for two or three months its useless.

                                                Anyway, so we thought we'd pick the high-risk population and we prove that there were still on high risk but when we could do something meaningful to extend their lives, so we thought we do not pick the worst patients we pick the patients that we think we can really help. We screened them well, we treated them well and we see if an ICD on the patient will benefit them. And that's why we picked the over 35% rage. You need another study to do below 35%, but I don't think that our results are substantiating such an effort.

Dr Mark Link:                     The population with EFs was 6-50%, which also has a high risk of sudden death in patients with dialysis but it’s still not looking with the population of less than 35%.

Dr J. Wouter Jukema:     No, I completely agree, and we acknowledge that in the manuscript, it was always in the manuscript within the revision that was also pointed out to us that it should be more clearly acknowledged, why we choose this patient population and finally, we can of course not make a formal recommendation on dialysis patients with an injection fraction of less than 35%. You can extrapolate data but we have no formal prof of course for this type of population. I fully agree.

Dr Carolyn Lam:                Before we go further, could you first describe, what did you find?

Dr J. Wouter Jukema:     Basically, the conclusions are the prophylactic ICD therapy in patients on chronic dialysis with an injection fraction of 35% or higher was not associated with a reduced rate of sudden cardiac death nor of all cause of mortality and besides that the preference of sudden cardiac death in this type of patients on dialysis was actually significantly lower compared to its reports from literature, so that's what we very often see of course if you fill out a death certificate, you have to fill out a cause of death and of course in many patients the heart stops, and you say it's a sudden cardiac death. But that's not what this study actually showed and finally it's also no authority that this population was not too healthy to see any benefit, if you look at the results over the years, then you'll see that after five or six years more than half of the patients are dead anyway, but due to all kind of causes and not to a sudden cardiac death.

                                                So, I think that this is from a pathophysiological background, this is also a very interesting study because we now have finally data, real data on sudden cardiac deaths in these types of patients.

Dr Carolyn Lam:                Indeed, and Mark, I know that you invited the editorial from Rod Passman, just discussing why did we see the results that we did. Not quite what we expected I suppose, what do you think Mark?

Dr Mark Link:                     First, I want to congratulate Dr Jukema for finishing this study, this was a massive task and a difficult and long one. I think I was surprised, there has been reported to be a very high rate of sudden death in dialysis patients regardless of their LDF. The ICD is very good at preventing sudden deaths, but not good at preventing other types of deaths, so I would extrapolate to say, well you can prevent sudden death in dialysis patients, you should prolong their life and this study did not show that at all. And I was surprised, and it just goes to what Dr Jukema was telling us, that what's reported on a death certificate as sudden death is not necessarily sudden death and could be other types of death and at the end all death is sudden.

Dr J. Wouter Jukema:     I fully agree with that remark because that makes is cumbersome to have the right interpretation of the data, so you have to feel like something and then finally your heart stops.

Dr Carolyn Lam:                What seems that most of the reasoning seems to be maybe a lower rate of sudden cardiac death than we expected, but there were also other factors that were considered, for example, if you could clarify by dialysis did you mean both hemodialysis as well as peritoneal dialysis, do you think that made a difference? For example, do you think ICDs work differently in presence of uremic precipitant of arrhythmias vs. not and so on, what do you have to say about those factors?

Dr J. Wouter Jukema:     We include on purpose both types of patients, the peritoneal dialysis and the hemodialysis patients because you could easily in-visit that there could be a difference, for instance to fluid or electrolyte sheaths that are more sudden in the hemodialysis patients than in peritoneal dialysis and we did a sub-analysis where we looked at both types, but the results are essentially the same, it doesn't seem to matter a great deal of what type of dialysis you have, the amount of sudden cardiac is lowered and expected. By the way occasionally, of course the ICD did work in sudden cardiac death, was aborted. So, it’s not that the apparatus doesn't function it does, it takes it properly and if functions properly. But finally, it doesn't prolong the life and you will die of something else, mostly infections in general well-being when finally, the nephrologist will say this is end of life you have to stop the dialysis procedures anyway.

Dr Carolyn Lam:                Right, great points, now in the last few minutes, I'm dying to ask, what do you think of the next steps from here. Mark, what do you think first? And then perhaps I'll give the last word to Wouter?

Dr Mark Link:                     I'll start with a question to Wouter myself, the question is what are we going to do now with the individuals on dialysis that are under 35%? I think this study has pretty clearly said that were not going to extend our CDs to people on dialysis with greater than 35%. But we still have a population that currently fits indication for a ICD if their expected longevity is greater than a year. And currently those people are included in the guidelines for ICDs, I think this study gives us some pause about what to do with our population. And many of that population are getting our CDs and I'd be curious to what Dr Jukema thinks about that population and whether that population warrants some randomized trial or whether we should continue with our current guidelines that recommend implantation of an ICD in any individual less than 35%, as long as their expected life span is greater than a year.

Dr J. Wouter Jukema:     I think these are excellent questions with excellent remarks, of course, finally, we do not know because we didn't investigate it, I can only imagine the difficulties we would have if we were to do a new additional trial with injection fractions patients less than 35%. I could tell you we had great great difficulty in persuading Nephrologists to take part in the study, because many of them were very reluctant, this is their principal, these are very ill patients, and a lot of them are more or less going towards the end of their lives so you cannot do this when we have Nephrologists telling us that they considered it an unethical study. A lot of them did not want to participate they said, "You shouldn't do this to this patient, they have troubles enough, they suffer from infections and all kinds of things."

                                                Having said this, I do not advocate that you should never implant an ICD in a dialysis patient, I think in our study we also clearly show that in dialysis patients, implantation of an ICD is feasible within acceptable although better complication risk and infection risk, so if you have a patient on dialysis where you feel this patient has a good life expectancy, for instance, he already suffers an episode of arrhythmia, I think you are entitled to discuss this with the patient and have it a try, it might work and prolong their life. So I would not say never do it, I think our studies show that you can do it, yes, it sometimes works but do not expect too much of it. You will never hear me say that in general you should not do it, if you have a clear indication for it you may do it, secondary effect may require a good reason, but primary prophylactic indication, that's a difficult one I think and to do this study in patients that are even more ill, with injection fraction of less than 35%, I feel will be exceeding the difficult.

Dr Mark Link:                     One other comment I have is the issue of the SUBCU ICD I think changes the equation in a bit because the risk of infection is much lower with a SUBCU IDC in patients on dialysis, did you have any SUBCU ICDs in your study or was it all transvenous?

Dr J. Wouter Jukema:     We don't have any data, when we designed and the developed study, the such a device was not even there so we couldn't do that, and during the study we did not adapt that but of course there is also no formal proof yet that it's a lot safer, a lot better, and once again this time of subcutaneous ICD I think you can do it at an acceptable complication rate. But it’s not effective enough, it's not that the patients were dying from infections of their ICD, they were dying of all kinds of infections and malignancies. Infections due to the ICD were facing procedures, real complications were rare.

Dr Carolyn Lam:                Great! Thank you Wouter, thank you Mark, what an important study and what a lot of lessons that we learned here.

                                                Thank you very much audience for listening as well, you've been listening to Circulation on the Run, don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019