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Circulation on the Run


Oct 31, 2022

This week, please join authors Kevin Roedl and Sebastian Wolfrum, as well as Associate Editor Mark Link as they discuss the article "Temperature Control After In-Hospital Cardiac Arrest: A Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the Journal and its editors. We are your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, very interesting, a randomized clinical trial of temperature control after in-hospital cardiac arrest. But before we get to that exciting study, let's grab a cup of coffee, and jump in and discuss some of the other articles in the issue. Carolyn, would you like to go first?

Dr. Carolyn Lam:

Yes. Starting with a great quiz. So Greg, which is better? How about this? It's multiple choice. Is it A; transradial, or B; transfemoral access, in terms of post-procedural mortality?

Dr. Greg Hundley:

I'm going to go with transradial. It has been, hopefully, I'm okay on this. It just seems so many fewer complications.

Dr. Carolyn Lam:

But that's exactly that we need to meta-analyze the studies that have been done. Exactly what this paper did, led by Professor Valgimigli, from USI in Lugano, Switzerland. So what they did is, they performed an individual patient data meta-analysis of 21,600 patients, enrolled in seven multi-center randomized control trials, comparing the transradial with transfemoral access, among patients undergoing coronary angiography with or without PCI. And they found that transradial access was associated with a lower incidence of the primary outcome of all-cause mortality, and the co-primary outcome of major bleeding at 30 days, compared to transfemoral access.

There was also evidence for reductions in major adverse cardiac and cerebral vascular events, net adverse clinical events, vascular complications, excess site bleeding, and blood transfusion. MI, stroke, and stent thrombosis, did not differ. And crossover was higher in the transradial access group.

At predefined subgroup analysis, the authors confirmed that the benefit observed the transradial group was generally consistent across the majority of pre-specified subgroups, except for those with significant baseline anemia. Patients with baseline anemia appear to derive a substantial mortality benefit with transradial access rather than transoral access, compared to those with mild or no anemia.

So, the authors concluded, that the meta-analysis provides evidence that transradial access should be considered the preferable access site for PCI, in patients with acute coronary syndrome, supporting most recent recommendations on the preferential use of this radial approach. So you were right, Greg.

Dr. Greg Hundley:

Very nice, Carolyn. A really important piece of science to disclose to our listeners, in that hurried state, and moving quickly door to balloon times, et cetera. And here we find another positive outcome in study result for transradial approaches.

Well Carolyn, as we know, my next paper, it's really going to come to us from the world of preclinical science. And it pertains to hypertension, which is a common cardiovascular disease, and is related to both genetic and environmental factors. But the mechanisms linking the interplay between the domains of genetics and the environment have not been well studied.

Now, DNA methylation, a classical epigenetic modification, not only regulates gene expression, but is also quite susceptible to environmental factors. Thereby, linking environmental factors to genetic modifications. So therefore, Carolyn, these authors, including Professor Jingzhou Chen, from Fuwai Hospital, National Center for Cardiovascular Diseases, and the Chinese Academy of Medical Sciences, and the Peking Union Medical College, and their colleagues, felt that screening differential genomic DNA methylation, in subjects with hypertension, would be important for investigating this genetic environment interplay in hypertension.

So this study, Carolyn, like many from the world of preclinical science and circulation, incorporated both human and animal model subjects. Methodologically differential genomic DNA methylation in hypertensive, pre-hypertensive, and healthy control individuals, was screened using the Illumina 450K BeadChip, and then verified by pyrosequencing. Plasma oviduct glycoprotein 1, or OVGP1 levels, were determined using an enzyme-linked immunosorbent assay. And OVGP1 transgenic and knockout mice were generated to analyze the function of OVGP1.

Dr. Carolyn Lam:

Wow. Nice approach, Greg. And what did the authors find?

Dr. Greg Hundley:

Right, Carolyn. These authors found a hypomethylated site at cg20823859 in the promoter region of OVGP1, and the plasma OVGP1 levels were significantly increased in hypertensive patients. This finding indicates that OVGP1 is associated with hypertension.

Now Carolyn, in OVGP1 transgenic mice, OVGP1 over expression caused an increase in blood pressure. Also, dysfunctional vasoconstriction, and vasodilation, remodeling of the arterial walls, and increased vascular superoxide stress and inflammation. And these phenomenon were exacerbated by angiotensin II infusion.

In contrast, OVGP1 deficiency, attenuated angiotensin II induced vascular oxidase, stress, inflammation, and collagen deposition.

Now pull down, and co-immunoprecipitation assays showed that myosin heavy chain 2A, or MYH9, interacted with OVGP1. Whereas, inhibition of MYH9 attenuated OVGP1 induced hypertension and vascular remodeling.

Dr. Carolyn Lam:

So Greg, let me try to summarize, is that okay? So hypomethylation, at that specific site in the promoter region of the OVGP1 gene, is associated with hypertension, and induces its upregulation. The interaction of this OVGP1 with myosin heavy chain 2A contributes to vascular remodeling and dysfunction. And so, OVGP1 is a pro hypertensive factor, that promotes vascular remodeling by binding to this myosin heavy chain. So, really cool stuff. Thanks for teaching us.

Dr. Greg Hundley:

Very good.

Dr. Carolyn Lam:

Well thanks so much, Greg. And we go back to the clinical world now, and ask the question, what is the efficacy and safety of prophylactic full dose anticoagulation and antiplatelet therapy, in critically ill COVID-19 patients? So I'm going to tell you the results of the COVID-PACT trial. And this was a multi-center, two-by-two factorial, open label, randomized controlled trial, with blinded endpoint adjudication in 390 ICU level patients. So, severely ill patients with COVID-19, from 34 US centers. Patients were randomized to a strategy of full dose anticoagulation, or standard dose prophylactic anticoagulation. And in the absence of an indication for antiplatelet therapy, patients were additionally randomized to either clopidogrel or no antiplatelet therapy.

Dr. Greg Hundley:

Ah, Carolyn. So what did they find?

Dr. Carolyn Lam:

Full dose anticoagulation substantially reduced the proportion of patients experiencing a venous or arterial thrombotic event, and there was no benefit from treatment with clopidogrel. Severe bleeding events were rare, but numerically increased in patients on full dose versus standard dose prophylactic anticoagulation, without any fatal bleeding events, GUSTO moderate or severe bleeding was so significantly increased with full dose anticoagulation, but with no difference in all-cause mortality.

So in summary, in a population of critically ill patients with COVID-19, a strategy of prophylaxis with full dose, versus standard dose prophylactic anticoagulation, but not the addition of clopidogrel, reduced thrombotic complications, with an increased risk of bleeding, driven primarily by transfusions in hemodynamically stable patients, with no apparent excess in mortality.

Dr. Greg Hundley:

Very nice, Carolyn. What a important piece of information, as many of us around the world are taking care of critically ill patients with COVID-19.

Well, how about we see what is in the mail bag this week? So first, Carolyn, there's a Frontiers piece by Dr. Packer, entitled, “Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 inhibitors, and Reaffirmation of the Nutrient Deprivation Signaling Autophagy Hypothesis.”

Next, there's a Research Letter, from Professor Airaksinen entitled, “Novel Troponin Fragmentation Assay to Discriminate Between Troponin Elevations in Acute Myocardial Infarction and End-stage Renal Disease.”

Carolyn, there's another Research Letter, from Professor Solomon, entitled, “Aptamer Proteomics for Biomarker Discovery in Heart Failure with Reduced Ejection Fraction.”

Also, Carolyn, [a] wonderful Cardiovascular News summary from Tracy Hampton, reviewing three articles. First, “Mechanisms Behind Cannabis Effects on Heart Health.” The second, “Exercise Inducible Metabolite Suppresses Hunger.” And then lastly, “Piezo1 Initiates the Cardiomyocyte Hypertrophic Response to Pressure Overload.”

Dr. Carolyn Lam:

Cool. There's also an exchange of letters between Doctors Jha and Borlaug on latent pulmonary vascular disease in therapeutic atrial shunt.

And finally, an On My Mind, by Dr. David Kass entitled, “What's EF Got To Do, Got To Do With It.” I love it. You must read it. It's so, so cool. All right. But now, let's go on to our feature discussion, shall we?

Dr. Greg Hundley:

You bet, Carolyn.

 

Welcome listeners, to our feature discussion today, and really delving into the world of in-hospital cardiac arrest, and how we manage those patients. And we have with us today, Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from University of Texas Southwestern in Dallas, Texas. Welcome gentlemen. Kevin, we're going to start with you. Can you describe for us, some of the background information that went into the construct of your study, and what was the hypothesis that you wanted to address?

Dr. Kevin Roedl:

Thank you, Greg. We thank you for the kind invitation to this podcast. We're very likened to do this podcast with you. And so, talking about the background of hypothermia in-hospital cardiac arrest, we have to go back like two decades almost, because there were two studies in New England Journal of Medicine published 2002, who introduced mild therapeutic hyperthermia to the treatment in post cardiac arrest. Primary, these two studies show the benefit of the therapy in this kind of patients. And then, 2003, it was introduced in also the international guidelines. However, these studies only addressed out-of-hospital cardiac arrest patients, and also, only shockable rhythms. And so, the question arised over the years, what about other patients like non shockable rhythms, or also in-hospital cardiac arrest?

And so, that's basically was the primary aim of our study to address this special population. Because when you see the states, the numbers, there are 290,000 in-hospital cardiac arrests a year. So it's actually, a very large population. And there's no randomized control trial to show any benefit, or maybe harm, in this group. There were some observational studies, 2016 in China published. From China, in this group, they looked at the Get With The Guidelines registry, and actually, they saw that there was probably a negative influence of hypothermia in the study. However, it was only observational. So actually, there were no randomized control trials. And that primary hypothesis was, that we wanted to know actually, does thus mild therapeutic hyperthermia work in this group of patients in the in-hospital cardiac arrest setting? And what is the outcome? Is it like in the out-of-hospital cardiac arrest setting, or not?

Dr. Greg Hundley:

Wonderful, Kevin. And so, can you describe for us then, your study population and your study design?

Dr. Kevin Roedl:

Yes, of course. We did a randomized control trial. There were over 1000 people screened, and overall, we included 242. So you see how hard it is to get people in there. And actually, in terms of hypothermic temperature control, we are 120 about, and long term at 118, and the final others of the endpoints. And when we look at the baseline characters of these patients, they were well balanced actually, about 72 years. When we look at the initial cardiac arrest rhythm, that's interesting because about 70% non-shockable rhythms, and 25% shockable rhythms. And probably also interesting, the location of the cardiac arrest. Medical boards about 50%, and ICU or ED was 22%. So that's probably summed up the baseline characteristics of our study.

Dr. Greg Hundley:

Perfect. And so Kevin, can you describe for us what was the hypothermic target for the group that was going to have their temperature recused?

Dr. Kevin Roedl:

Yes, hypodermic target was 32 degrees to 44. And so two degrees Celsius, basically the same target like in earlier trials.

Dr. Greg Hundley:

Very nice. Well listeners, now we're going to turn to our second co-author, Dr. Sebastian Wolfrum. And Sebastian, can you share with us the study results?

Dr. Sebastian Wolfrum:

Yes, Greg. Thank you very much for the opportunity to participate in this podcast. Only wanted to include unconscious patients, and therefore, we took a time and took 45 minutes after their cardiac arrest, to let the patients get away if they did so. We also excluded patients that had severe functional deficit before the cardiac arrest; since we could not really define the neurological outcome if we would've included those. And we didn't see any differences. Neither in mortality, not in the functional outcome, either when they're treated with 33 degrees Celsius, or whether normothermia was used.

The death rate after six month was in a range which is comparable to other in-hospital cardiac arrest studies, and higher than those performed in the out-of-hospital cardiac arrest studies. It was about slightly over 70% in both groups. And the number of patients with the good functional recovery after six months was 23% of the patients in the hypothermia group, and 24% of the patients in the normothermia group.

And if we look at only the survivors, we see that the ones which are worse functional outcome, were most of them dead after six months. We then also focused on the temperature curves in our patients, and to see whether we have achieved our goal. And we saw that we have reached the target temperature within four and a half hours after cardiac arrest in our hypothermia group. Which is not as fast that we had expected, but still in the range, which is comparable to other studies on this field. And we also saw that our control group was about 37 degrees, within the first 12 and 48 hours. So we truly avoided fever, which has not been done in every previous study on cardiac arrests.

Dr. Greg Hundley:

Very nice. And any differences between the hypothermia and normothermia groups, related to the age of the patient? Or, whether or not they had a shockable rhythm at the time of presentation?

Dr. Sebastian Wolfrum:

We saw as a result of our study, that age is a predictive factor for mortality. But age did not differ between our treatment groups, and therefore, did not interfere with our results. And we didn't see differences in the shockable or non-shockable rate in our patients in the different treatment groups.

 

Dr. Greg Hundley:

Thank you. Well listeners, now we're going to turn to our associate editor, Dr. Mark Link, one of our expert electrophysiologists at Circulation. And Mark, you have many papers come across your desk, and what attracted you to this particular paper?

Dr. Mark Link:

There were a number of things. One, it's hard to do RCTs in resuscitation, and I thought they did a very nice job with this RCT. Two, the subject of hypothermia, or therapeutic temperature management, is a very hot one in resuscitation. It's one of the few treatments in the past that have been shown to make a difference in outcome. And so, all of those trials were done in out-of-hospital arrest. So to have a trial done in in-hospital arrest was very intriguing also.

And I think we're all disappointed that it wasn't a positive trial, but we have to take the negative trials also. And I think, part of the reason it may have been a negative trial is because the normal thermic group avoided hyperthermia. And I think that's something that's coming out of a lot of these trials is avoid fever. It may not be so important to get hypothermic targets, actually, looks like it's probably not, but it looks like it's very important to avoid fever.

Dr. Greg Hundley:

Very nice. Well listeners, we're going to turn back to our expert panel here really, and start with you Kevin. Kevin, what do you think is the next study that needs to be performed in this sphere of research?

Dr. Kevin Roedl:

Thank you for this interesting question. Yeah, a bunch of studies could be performed, especially maybe in the out-of-hospital cardiac arrest study, because we don't know. This fever harmful, we have to find certain subgroups in which this treatment works. So maybe in this subgroups there is data on this and it could be a benefit. So these are, I think, the two main topics that should be done in the future.

Dr. Greg Hundley:

Thank you. Sebastian, what are your thoughts?

Dr. Sebastian Wolfrum:

As Mark said, the hypothermic treatment was, for decades, maybe the only treatment which we could give to cardiac arrest patients, which has been proven to reduce mortality. And all other studies following didn't see any be benefit of hypothermia, not even in a subgroup. Also, the TTM trials did not. So I'm questioning myself, where is the original HACA study group that benefits? Where did this hide in the other studies?

So I would think, to do another study in out-of-hospital cardiac arrest patients, whether in ventricular fibrillation that had shown in the HACA trial to reduce mortality. This should be done in a similar way to the original study, to see whether there is this subgroup. People who support the idea of hypothermia also focus very much on the fast onset of their hypothermic treatment. And they say we saw a difference in mortality in the HACA trial, and we could very fast. And I think the other studies have to show that they cool as fast as the HACA study. So the main focus should be on the time calls of hypothermia after cardiac arrest, cooling very fast to a target temperature of 33 degrees, maybe holding on for 24, maybe 48 hours.

Dr. Greg Hundley:

Very nice, Sebastian. So focusing on the speed and the timing of that cooling. And Mark, anything to add?

Dr. Mark Link:

Yeah, so if I sit here with my writing group hat on for the HA and say, "What are we going to do for the resuscitation guidelines in 2025?" I think you look at the totality of the data for targeted temperature management. And I think, the main thing you say, walking away from this, is avoid fever. Don't let your patients get hot. I'm not sure you can say much more than that right now, until we get more data.

Dr. Greg Hundley:

Very nice. Well listeners, a really interesting provocative discussion today. And we want to thank Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from Dallas, Texas, bringing us the results of this study highlighting that hypothermic temperature control is compared with normothermia did not improve survival, nor functional outcome, at 180 days in patients presenting with coma after in-hospital cardiac arrest.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On The Run.

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.