Bob Underwood, MD (Host): Welcome to Pedscast, a podcast brought to you from Children's of Alabama. I'm your host, Dr. Bob Underwood. Joining us today is the Associate Professor and Medical Director of Cardiac ECMO, a Division of Pediatric Cardiology at Children's of Alabama, Dr. Jonathan Byrnes. Dr. Byrnes will help us explore the unique aspects of a multicenter anticoagulation study and help us understand the reasons behind the evolving use of bivalirudin in extracorporeal membrane oxygenation and unravel the complexities of conducting a cooperative study across multiple medical centers. Dr. Byrnes, welcome to Pedscast.

Jonathan Byrnes, MD: Hey, good morning, Dr. Underwood. Thanks for having me on this morning.

Host: Yeah, absolutely. So, what made this particular study unique?

Jonathan Byrnes, MD: So in the past, the change from heparin to bivalirudin has been done at individual centers and it's been more or less a decision by an institution to change from one therapy to thin the blood while patients are on extracorporeal support to another. And they would report their outcomes. To do so in a more controlled manner, that we brought six centers together, and that we ended up just observing our outcomes that ended up occurring, but we would end up case matching them, be able to have a better idea of what the outcomes are, and be able to control the wide degree of variability in patients that require ECMO.

Host: Yeah, and bring those components together so you understand. So, bivalirudin, it's not really a new drug. So, why is it gaining traction specifically for use in pediatric ECMO now?

Jonathan Byrnes, MD: I really think that what's really driven that was the success of using it in pediatric VAD support, or Ventricular Assist Device. Whenever the initial reports were coming out about 10 years ago with the Berlin Heart, the rate of stroke was 25 to 30 percent, whenever patients were on pediatric ventricular assist devices. Through the work of the Action Network, they've done a great job of bringing the teams together from across the country and actually internationally to end up having similar standards in how they anticoagulate and treat patients with severe heart failure and on VADS. And one of those measures they used, was to measure stroke as there ended up being a shift from use of heparin to use of bivalirudin and based on the most recent data, that the stroke rate's gone down to about five to 8% with the use of bivalirudin. So that's garnered a lot of excitement, amongst the pediatric cardiac intensivist and applying bivalirudin more.

Host: Yeah, well, that's an incredible improvement in the stroke rate with that kind of information. So, six medical centers were part of this particular study. What does it take to conduct this level of cooperation across several medical centers?

Jonathan Byrnes, MD: Really, the credit needs to be given to Dr. Mohamed Hamza. He's a physician that I'd worked with in the past, but he trained with several people whenever he was in Milwaukee and those individuals ended up spreading out to different centers over the country. And so it was through his leadership and through his personal connections and his hard work that he was able to bring everybody together.

And from there that we were able to do a particular type of case controlled study called a utilized propensity score matching in order to minimize the amount of variability between patients that were on bivalirudin and heparin.

Host: That takes a heck of a lot of coordination from Dr. Hamza. Great job. This is, so what were the key findings of this multi center anticoagulation study?

Jonathan Byrnes, MD: The most important findings was that there was less mortality in the patients that were on bivalirudin than on heparin. Surprisingly, we found a difference in neurological outcome and there was also more bleeding and more thrombosis of the ECMO circuit whenever patients were anticoagulated with heparin.

This is rather surprising because the patients that were on bivalirudin actually, had higher levels of their PTT as opposed to the heparin patients. So it seems that there's something intrinsic to bivalirudin that allowed for a better biocompatibility of the patient's blood to the ECMO circuit.

Host: Yeah, heparin's, you know, it's been the standard for so long. It's incredible to find the end of these findings with bivalirudin. Again, not necessarily a new medication, but new findings. So how are these different? I mean, we kind of talked a little bit about decreased mortality, increased bleeding in the heparin patient. So, how are these findings really different from the other anticoagulation studies that have been done?

Jonathan Byrnes, MD: So that there had been a handful of studies, but again, that they were always single center and there was a lot of heterogeneity in how bivalirudin was applied. So the majority of the studies ended up showing in the past that bivalirudin allowed for less mortality. Occasionally it would show that there was less blood product utilization, but I think that given that our study was the largest to date; that we ended up just having the sheer numbers to show the full benefit of utilizing bivalirudin as opposed to heparin.

There were studies that ended up showing no difference, but I think this just further substantiated what had been seen in other studies in the past.

Host: That's phenomenal. So, what's the impact for patients at Children's of Alabama? What's this going to mean for the patients?

Jonathan Byrnes, MD: We believe that it will end up allowing for less bleeding and fewer blood transfusions, and a lower mortality for patients that are supported on ECMO. However, that is exciting and one sided our results were; it was a retrospective study, and so to truly change the standard of care that we're going to end up needing a randomized controlled trial. There is some heterogeneity that persists in between our application of bivalirudin versus heparin based on physician preference and what their comfort level is. But overall, the team's starting to see the benefits of bivalirudin.

Host: So, are there plans right now for the prospective trial to do it in a randomized fashion? And would Dr. Hamza be part of that?

Jonathan Byrnes, MD: We've talked about it, but I think that there's interest, but the coordination hasn't come about yet. I think that there's interest in doing that on multiple fronts, and most likely that that would be coordinated through the Extracorporeal Life Support Organization or ELSO, just to be able to gain more buy in. There's plans for that, but there's nothing underway at present.

Host: Wow. Great plans for the future though and, you know, huge impact for patients in the long run too. So as we're concluding, anything else you'd like to add to the conversation about this?

Jonathan Byrnes, MD: I think this was a very exciting study with exciting findings. And hopefully that we'll be able to get started on a randomized controlled trial soon. But based on our retrospective methods, there could have been certain centers that ended up having a higher mortality rate or had more bleeding events that tended to use more heparin that may confound our study findings.

So, before saying that this is the way to do things, that we really need to have the prospective data.

Host: You bet. Well, thanks for joining us today and thanks for shedding light on the multicenter anticoagulation study.

Jonathan Byrnes, MD: Absolutely. Thanks for having me. Have a good day.

Bob Underwood, MD (Host): For more information, or to refer patients to Children's of Alabama, visit childrensal.org. That concludes this episode of Children's of Alabama Pedscast. If you found this podcast helpful, please subscribe and review it. And be sure to share this podcast on your social channels. And be sure to check out the entire podcast library for other topics that might be of interest to you.

Thanks for listening. I'm your host, Dr. Bob Underwood.