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Circulation on the Run

May 13, 2019

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 of Circulation from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Are NOACs, or non-vitamin K antagonist oral anticoagulants, safe and efficacious in patients with extremely high or very low body weight? Very interesting paper and discussion coming right up. Greg, I hear that you've got a couple of papers you'd like to highlight first.

Dr Greg Hundley:             You bet, Carolyn. My two papers today both focus on ventricular dysrhythmia. The first one, from Yuki Komatsu from Tsukuba, Japan, researches the efficacy of catheter ablation of refractory ventricular fibrillation storm after myocardial infarction. VF storm attributed to focally triggered VF after MI is recognized as a distinctive, lethal, arrhythmogenic syndrome that differs from scar mediated monomorphic VT.

                                                This study investigated the acute and long-term outcomes of catheter ablation for the treatment of last resort in a large series of consecutive patients with post-MI VF storm refractory to medical therapies. In the study, investigators enrolled 110 patients averaging about sixty-five years in age. Ninety-two were men, and their average ejection fraction was approximately 31%. VF storm occurred in the acute phase of MI, about four and a half days after MI-onset, during the index hospitalization in about 39% of the patients. It was sub-acute (that is greater than 1 week later) in 44% of patients. It was remote (greater than 6 months later) in 17% of patients. And the focal triggers were found to originate from the scar border zone in 80% of the individuals.

Dr Carolyn Lam:                And what did the study show?

Dr Greg Hundley:             So Carolyn, during in hospital stay after ablation, VF storm subsided in 84% of patients and overall, 27% of in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality, with a P-value of 0.008. During follow-up after discharge from the hospital, only one patient developed recurrent VF storm. Of note though, 36% of the patients died, with a median survival of 2.2 years. And the long-term mortality was associated with a low EF (less than 30%), New York Heart Association class greater than 3 Heart Failure, a history of atrial fibrillation or chronic kidney disease.

                                                So in summary Carolyn, the results of this study show that in patients with MI presenting with focally-triggered VF storm, catheter ablation of the culprit triggers is life-saving and appears to be associated with short and long-term freedom from recurrent VF storm. The overall mortality for these patients is associated with the severity of their underlying cardiovascular disease, and those associated co-morbidities.

                                                Now my next paper is from one of our associate editors, Sami Viskin from Tel Aviv University. He's looking at a new form of polymorphic VT. Now as we think about polymorphic VT, I always think about the long QT interval syndromes associated with Torsades de Pointes. We have specific management strategies for those long QT syndromes, but Carolyn, there's a second category of polymorphic VT that's not related to QT prolongation. This second category involves patients without structural heart disease, who have genetic disorders like Brugada or patients that may have experienced hypothermia. There is also a third category of individuals with structural heart disease, during acute ST elevation MI.

                                                What Sami has discovered is there's now a fourth category of non-QT prolongation, which includes those with coronary artery disease but without evidence of ischemia.

Dr Carolyn Lam:                So how did they show or find this fourth category?

Dr Greg Hundley:             Well, this is a longitudinal cohort that he identified, and they basically followed forty-three individuals who developed polymorphic VT within days of an otherwise uncomplicated MI or coronary revascularization procedure. The in-hospital mortality was 17% with these patients with arrhythmic storm and the patients were treated with quinidine invariably survived to hospital discharge, just like the other categories of non-QT prolongation polymorphic VT.

                                                During long term follow-up of five and a half years, 16% of patients discharged without quinidine developed recurrent polymorphic VT and there were no recurrent arrhythmias in those individuals that were receiving quinidine therapy long term.

                                                So Carolyn, although quinidine therapy is usually considered contraindicated in patients with organic heart disease who develop ventricular arrhythmias, this therapy may be life-saving for patients with coronary disease developed arrhythmic storms due to polymorphic VT. Polymorphic VT storms may be a transient phenomenon. It's unclear for how long quinidine should be continued in these responsive patients.

Dr Carolyn Lam:                Wow, neat! Well, for my two papers I'm going to start off with a basic paper and, in fact, a quiz for you this time, Greg! So, what do cilia have to do with the heart? All right, you get to ask me, do you remember what cilia are?

Dr Greg Hundley:             Aren't cilia on prokaryotes? I mean, I think of bacteria.

Dr Carolyn Lam:                All right, let me set us straight. The primary cilium is a cellular organelle and it's formed by a protrusion of the plasma membrane that functions as a signaling platform in eukaryotic cells and is found in many cells including neurons, pre-adipocytes and kidney tubular cells, where they have been reported to be involved in a variety of cellular functions such as proliferation, differentiation, cell cycle regulation as well as mechano-chemical sensing of diverse stimuli.

                                                Now, the importance of these cilia is highlighted by the role in several diseases, known as ciliopathies. Polycystic kidney disease is one such disorder with, by the way, numerous cardiovascular manifestations. Whereas ciliated cells have been described in the developing heart, a role for primary cilia in the adult heart has not been reported. It was therefore the aim of these authors and those co-corresponding authors Dr Hill from UT Southwestern and Dr Lavandero from University of Chile, who aimed to identify cells in the adult heart harboring a primary cilium and to determine whether these primary cilia play a role in disease-related remodeling.

Dr Greg Hundley:             Carolyn, this is so interesting. I had no idea about these cilia. So what did they find?

Dr Carolyn Lam:                So, in a series of elegant experiments, these authors identified for the first-time primary cilia in mouse, rats, and human hearts, specifically and exclusively in cardiac fibroblasts. Now these ciliated fibroblasts were enriched in areas of myocardial injury. Transforming Growth Factor beta-1 signaling and SMAD3 activation were impaired in fibroblasts that were depleted of the primary cilium. Extra cellular matrix protein levels and contractile function were also impaired. And in vivo depletion of PC1 inactivated fibroblasts after myocardial infarction impaired the remodeling response.

Dr Greg Hundley:             So how do we use this clinically, and what does it mean for us?

Dr Carolyn Lam:                These findings point to a pivotal role of cilia and PC1 in disease related pathological cardiac remodeling and suggest that some cardiovascular manifestations of autosomal dominant polycystic kidney disease, for example, derive directly from myocardium autonomous abnormalities. The findings also uncover novel fibrosis regulators and raise the prospect that this pathway may emerge as a target with therapeutic relevance.

Dr Greg Hundley:             Wow, very interesting!

Dr Carolyn Lam:                Thanks! And the next paper is also very interesting, in dilated cardiomyopathy and providing insights in how specific viral function may be involved in the development of dilated cardiomyopathy. Looking at the Group B enteroviruses, which are a common cause of acute myocarditis and can be a precursor of chronic myocarditis and therefore dilated cardiomyopathy leading to heart transplantation. In fact, enterovirus-induced dilated cardiomyopathy represents a third of idiopathic dilated cardiomyopathy cases.

                                                So these authors, led by corresponding author Dr Andreoletti from University of Reims, Champagne-Ardenne and Dr Semler from University of California, performed deep sequencing of viral RNA from cardiac tissue from patients with enterovirus related end stage dilated cardiomyopathy and then trans-factored viral RNA clones, mimicking the viral genomes found in patient tissues into primary human cardiac cells to assess their replication activities and impact on cardiomyocyte function.

                                                They found that the major persistent viral forms are composed of B-type enteroviruses harboring 5' terminal deletion in their genomic RNAs. These viruses alone, or associated with full length populations of helper RNAs, could impair cardiomyocyte function by viral enterovirus proteinase 2A activities in these enterovirus-related dilated cardiomyopathy cases.

Dr Greg Hundley:             Very interesting, Carolyn. So what are the clinical implications of this viral infection of the heart?

Dr Carolyn Lam:                Well, the findings seem to imply that it would be important for us to develop specific inhibitors of enterovirus proteinase 2A activity that might prevent viral replication and inhibit the shut-off of host cell translation as well as the disruption of dystrophin.

                                                Furthermore, in early diagnosed enterovirus induced dilated cardiomyopathy, the use of such protease inhibitors could potentially decrease and stop the chronic pathological process of dilated cardiomyopathy and therefore reduce the need for heart transplantation in this end-stage. Very interesting, but requires more work.

                                                So, that wraps up our summaries Greg. Shall we move to our feature discussion?

Dr Greg Hundley:             Absolutely.

Dr Greg Hundley:             Today we have Renato Lopes from Duke University in Durham, North Carolina and Brian Olshansky, Professor Emeritus from Iowa now in clinical practice in Waterloo and Mason City, Iowa. We're going to talk about our non-vitamin K oral antagonists, or NOACs, safe and efficacious in patients in extremely high (greater than 120 kg) or extremely low (less than 60kg) of body weight.

                                                Renato, welcome to our podcast in Circulation on the Run. Can you give us a little overview of your study, why you performed it and what results did you experience?

Dr Renato Lopes:              The idea behind this study was to provide more data into the use of NOACs in these extreme body weight patients, where we don't have a lot of information. Some guidelines actually caution against the use of NOACs in patients with extreme body weight because of the lack of data.

                                                We had the opportunity to look at the Aristotle database, which was a large, randomized trial comparing apixaban versus warfarin for patients with atrial fibrillation, over 18 000 patients. We took advantage of this database to try to look at the extreme body weight and how those patients at weight more than 120 kg, more than 140 kg and less than 60 kg, performed in terms of the treatment effect of apixaban versus warfarin. This was the rational, to try to provide more data so people could gain additional confidence in using apixaban in clinical practice in those extreme body weight patients.

                                                What we showed was, in general the treatment effect of apixaban versus warfarin for the efficacy outcomes CHOKE, systemic embolism and all cause death and myocardial infarction was very consistent across the weight spectrum and preserved. Apixaban was superior to warfarin and this was consistent regardless of the weight category. For the low body weight patients less than 60 kg, we also found that apixaban results in terms if efficacy was preserved.

                                                So, going out to the bleeding and safety endpoints, apixaban was safer than warfarin across different spectrums of weight. Surprisingly, in patients less than 60 kg we saw an even greater relative risk reduction in bleeding, in patients treated with apixaban compared to warfarin. The main message was for efficacy, apixaban was better than warfarin - the same results as the Aristotle main trial. For bleeding and safety endpoints, we also saw the same results and consistent results with apixaban- in particular with patients below 60 kg, which is always a concern that people might have in clinical practice. It seems that apixaban was even safer with an even greater treatment effect.

Dr Greg Hundley:             Very nice. Can you tell us a little bit about some of the sites where you enrolled patients and did you identify any variation in age, sex or region specific factors? Were there any differences in your findings related to race?

Dr Renato Lopes:              That is a very interesting question because we know that these variables play an important role in body weight. We enrolled patients from thirty-nine countries in Aristotle, in over a thousand sites all over the world. Interestingly, I can tell you that the heaviest weight we had in our study was 205 kg, a patient from the United States. The lightest weight that we had was 39 kg, from the Philippines. You lose trading the variation that regions of the world can play out and how patients can perform. We haven't seen any major difference in these analogies. There were prior analogies that look at different BMIs, and we know that the treatment effect might be attenuated depending on race and sex. In this analogy, we did not find any significant difference according to race, region of the world or even sex.

Dr Greg Hundley:             Just getting back to your body weight measurement, you mentioned percentage of individuals were above 120 kg and briefly mentioned some were above 140 kg. What percentage of your study cohort was that extra-large size, above 140 kg? Do you think more work needs to be done in that area or do you think the results were sufficient for that very heavy body weight?

Dr Renato Lopes:              This is a very important question. If we look at the breakdown, we had about 11% of the entire trial in the low spectrum of weight, less than 60 kg in weight - almost 2000 patients. A good number of patients. In extreme weight more than 120, we have about 980 patients. That was 5.5% of the overall trial. When you look at greater than 140 kg, we had 258 patients, 1.4% of the overall trial population and about 25% of this category greater than 120.

                                                I think as we start getting greater than 140 kg, we had 258 patients. It is not a large number of patients. It is some information and it is good to have some data on these patients. Before that, we had no data on apixaban in this level of weight. What we are seeing is that above 140 kg, the death rate are very low. There is a trend to better bleeding endpoints and better bleeding profile with apixaban, similar to what we have seen in the entire spectrum of weight when we look at weight as a continuous variable. We also saw that trend in patients greater than 140 kg for bleeding. This is reassuring. I don't think we can say it is definitive, it is only 260 patients that we are talking about.

                                                It is reassuring that we now have data in patients more than 140 and up to 205 kg, and we didn't seem to see any major concern or any difference in the curves in terms of the direction of efficacy and safety of apixaban. For the majority of patients it is reassuring and gives us extra confidence that the dose we use in clinical practice five milligrams twice daily should also work in those heavy weight and the heaviest body weight patients.

Dr Greg Hundley:             Very good. Brian you've done an excellent editorial and I wonder if you could help us put this study in perspective with what we know about NOACs and managing patients with atrial fibrillation?

Dr Brian Olshansky:         It really is a fascinating study. Obesity is as growing problem for us here in the mid-west and probably throughout the world. It effects a variety of things including drug pharmakinetics, volume of distribution, drug clearance etc. So knowing how NOACs work at the extremes of body weight, either the massively obese or the vanishingly frail, it becomes important to understand the safety and efficacy of the use of NOACs in these individuals. There are guidelines that caution us against use of NOACs at extremes of body weight, particularly those patients who are over the 120 kg mark. The one point I would like to make is, at least here in the mid-west, 120 kg is becoming almost the norm. We are having people that are becomingly massively obese and this is really the question then in my mind, is what to do with those patients who are over 140 kg or even way more than that. This gets to points that I would like to make about some the issues we need to consider about this study and where we are with our understanding about the use of NOACs in the extremes of body weight.

                                                One thing to keep in mind is, in this analysis, this was a retrospective group analysis. That is one important point. We don't have prospective data that look at an entire large population, a very frail, a very low body weight population.

                                                Another issue is that weight is not a static measure. We only have assessment at the baseline. Variability in weight or body mass index may be important in terms of its relationship to the development of atrial fibrillation and sequelae. The other issue here to consider is that there are comorbidities that are associated with those who are at the extremes of body weight and there was a significant variation in this study in age composition, sex dominance, the region of enrollment, the presence of comorbidities between the different weight groups that could contribute to results we have seen. Those with low body weight had more comorbidities and a higher mean CHADSVASC score, and had the biggest difference between apixaban and warfarin.

                                                We have quite a bit to learn about how to understand these data, and when we consider the individuals who are over 140 kg, indeed there are concerns about the volume of distribution of a NOAC and its efficacy. We would like to rely on this data. The problem is that the number of individuals that are a part of this retrospective analysis at the very high body weight and very low body weights was a rather small number and so to project from that number, what we should do with all of our patients becomes somewhat of a concern.

                                                Although these are interesting and provocative data, what we really need is to have some well-designed large prospective randomized controlled trials that specifically address those individuals at the extremes of body weight because this is becoming more and more of a problem as time goes on. We are seeing more individuals that are at the extremes of body weight. While I have not specifically noticed a difference in my own clinical practice, what we need is a better understanding about the dosing of and potential risks and benefits of the NOACs for the extremes of body weight.

Dr Greg Hundley:             On behalf of Carolyn and myself, we really appreciate you listening. Have a great week. We look forward to seeing you next week.

Dr Carolyn Lam                  This program is Copyright American Heart Association 2019.