#400 - 🔵 [NEO CONFERENCE] - What Are the Unintended Consequences of Ignoring a PDA

Hello friends 👋

In this live episode from the Neo Conference in Las Vegas, we welcome back Dr. Souvik Mitra to unpack the evolving landscape of PDA management in extremely preterm infants. We dive into the recent AAP guidelines recommending against early medical treatment and explore potential unintended consequences, including rising transcatheter closure rates and delayed intervention. Dr. Mitra shares his institution's approach using the SMART-PDA criteria, highlighting the importance of treatment timing and proper patient selection. Join us for a nuanced discussion balancing large pragmatic trial data with bedside clinical judgment for our most vulnerable babies.

Link to episode on youtube: https://youtu.be/aiAKEf_jLnw

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Short Bio: Souvik Mitra (pronounced "Show-vik Mit-ra") is a Neonatologist and Associate Professor of Pediatrics at the University of British Columbia and a Clinician-Scientist at BC Children's Hospital Research Institute. He completed medical school and pediatric residency at Calcutta Medical College in India before moving to Canada, where he pursued fellowship training in Neonatal-Perinatal Medicine and an MSc in Clinical Epidemiology from McMaster University, followed by a PhD in Epidemiology and Applied Health Research from Dalhousie University. He is trained in targeted neonatal echocardiography and serves on the RCPSC Area of Focused Competence Subcommittee in Neonatal Hemodynamics. His CIHR-funded research focuses on improving outcomes for extremely preterm infants with patent ductus arteriosus through multicenter clinical trials. He holds leadership roles with the Canadian Neonatal Network, the Canadian Pediatric Society, and the Cochrane Neonatal Group. Outside of medicine, he enjoys traveling with his family and playing cricket.

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The transcript of today's episode can be found below 👇

Ben Courchia MD (00:00.174) Hello, everybody. Welcome back to the Incubator Podcast live at Neo Conference in Las Vegas. We are joined this afternoon by good friend Souvik Mitra. Souvik, welcome back to the podcast.

Souvik Mitra MD (00:10.094) So glad to be back with you guys.

Ben Courchia MD (00:13.098) Same, same. You had an exceptional session this morning on the PDA.

Souvik Mitra MD (00:19.822) Yes, yes.

Daphna Yasova Barbeau MD (00:22.296) He's like, yeah, it was exceptional. You gave a lecture, your lecture was Medical Treatment of the PDA: Current Thoughts. And then you were followed by Dr. McNamara, Precision in the Care of Infants Undergoing Transcatheter PDA Closure. But we'll start with your lecture first. What are some of the take-home points? You were discussing a predictable, potential controversy for us coming up.

Souvik Mitra MD (00:49.068) Yes, and we brought that up a few times previously as well, the impact of the recent AAP statement on clinical practice.

Daphna Yasova Barbeau MD (01:00.078) For people who don't know what the statement says, you can catch us up.

Souvik Mitra MD (01:03.722) So just to highlight one recommendation from the statement, it says very rightly, based on existing pragmatic trial evidence, that early or very early treatment doesn't make any difference in clinical outcomes. So treatment within the first 14 days in preterm infants is not recommended. In my lecture, I took a deep dive into the evidence and tried to demonstrate the nuance of how the smallest and sickest babies were probably not represented in many of the trials, issues around diagnostic precision, and the fact that maybe in some babies, in a select population, an earlier treatment within a therapeutic window where the drugs actually work may be beneficial. But regardless, coming back to the statement, it's out there, people are using it or trying to use it. My worry with that is that people will ignore, not ignore, as Ben said, they will look at PDAs but not treat PDAs in the first two weeks.

Ben Courchia MD (02:17.452) I hope that people are still going to look at the PDAs.

Souvik Mitra MD (02:19.918) I am skeptical. So essentially what will happen is that the medical treatment of the PDA in the first couple of weeks, regardless of the gestation, regardless of the clinical severity, might go down. But the PDA problem is not going to go away in the smallest and sickest babies. So then these clinicians would now, after two weeks, jump on medical treatment because it's still there.

Ben Courchia MD (02:48.718) Now they're allowed.

Souvik Mitra MD (02:50.122) Now they're allowed, but now the medications don't work. So they will try one course, a second course, it doesn't work, and then these babies will end up getting a cath closure. So my worry is that with this blanket statement to not treat PDAs in preterm infants, regardless of how preterm they are or what their clinical status is, the treatment exposure might actually go up. And your cath closure rates will also go up. What we have found in our center, when we have moved to a more selective early treatment approach, and we presented that in our local conference earlier in January, that our treatment rates have actually gone down. We hardly treat babies more than 26 weeks. Less than 26 weeks, we treat a select population of babies early on. And since we are treating them within a specific time window early on, the drugs actually work. So we don't have to expose them to multiple medications.

Ben Courchia MD (03:51.97) Can you elaborate? I think people should know about the effectiveness of the medications within certain time windows. I don't want people to get the misrepresentation that the drugs work less. There's a clear association with the effectiveness of the medications and the timing of the administration. Can you talk a little bit about that? Because I think there are certain time points that are important to know when we talk about medically treating the PDA, specifically day 7, day 14, day 28, and the curve is quite impressive as to how effective... Can you just inform the audience a little bit more about that?

Souvik Mitra MD (04:23.758) Absolutely. So I'll just talk about new clinical data that is coming out. So I think you've discussed the TREOCAPA trial, the trial on prophylactic acetaminophen, right? It came out last week. They randomized extremely preterm infants to prophylactic acetaminophen within the first 12 hours versus placebo. If you look at PDA closure rates in the trial overall, it was 70% with acetaminophen. In the 23 to 26 weeks gestation age group, it was 60%. If you look at data from observational studies, say from our own comparative effectiveness study, where babies were exposed to acetaminophen at a median of eight days, the effectiveness was 50%. So it falls off. The same thing happens with ibuprofen. If you look at randomized trials, regardless of the mean gestational age of enrollment, the median age of treatment was around three days. And the effectiveness was around 70%. But if you look at observational studies, especially studies that have treated babies later, the effectiveness falls off. So the point is that if you have to choose to treat a baby, then treat a select group early on. The last thing that you want to do is wait for two weeks. If you have made a conscious decision to ignore the PDA for two weeks, then don't chicken out after two weeks and expose babies to medications. Then bite the bullet. You know that a lot of your babies may end up getting cath closure, but just stick to your guns.

Ben Courchia MD (06:15.426) I obviously have a lot of interest in this particular topic, so I'm going to pretend to be the other side of the argument so that we have a fun conversation. I would tell you, Dr. Mitra, you are so keen on wanting to close the PDA. The transcatheter closure is 100% effective or close to it. What's so bad about that?

Souvik Mitra MD (06:36.394) It's 100% effective, but you also need to look at what adverse effects come with it. And that is center-dependent, expertise-dependent. Dr. McNamara has shown nicely in his recent paper that there's a huge difference in serious adverse effects, including death and other adverse effects, between high-volume centers and low-volume centers. And that is something that you cannot ignore. If you ask a parent, would you want to take the risk of a medication that might give you a 60 to 70% chance of closure with lesser adverse effects versus don't even bother about that, go for a 100% effective cath closure if needed later on, but it comes with serious adverse effects. It'll be a very interesting conversation with parents.

Ben Courchia MD (07:29.378) Yeah, and I also think that one of the things that is not spoken about when we talk about transcatheter closure is the side effects that we don't know about. I think that we don't really know what it means when you take a shunt that has been open for days, close it within a second, and then how the baby's body adapts to that sudden change in hemodynamics.

Souvik Mitra MD (07:52.494) Absolutely. And that's the reason why you would find these cases post-cath closure. In some cases you have this evolving LV dysfunction leading to pulmonary edema. And there's a nice paper showing that the lung ultrasound pre-cath closure shows congested lungs, drops off, remarkable improvement post-cath closure. Six, eight hours later, goes back to where it was. Because there is redevelopment of pulmonary congestion because the left heart is struggling. And there is diastolic dysfunction and you need to address that. So there are those complications as well.

Daphna Yasova Barbeau MD (08:32.142) I just want to touch on the family perspective. I think some people, if you're a trainee or at a major institution, you assume you could get a catheter closure any time of day, any day of the week. For many institutions, that also means transport for the baby at most institutions.

Souvik Mitra MD (08:49.95) Absolutely, absolutely. And that's a hugely important point that you're talking about. If you want to have success with minimal side effects, then you are having to transfer that patient to a high-volume center, which also brings in all the complications, logistical and otherwise, of transporting a baby. So that has to be taken into account as well. There are unintended side effects not only at a patient level but also at an institutional level that you need to consider if you are going down the route of not medically intervening at all and going for cath closure in a select population of babies. So that is something that you have to think about. And the other thing is that more and more of these 21, 22-weekers are surviving. And you cannot just stick a cath in those babies early on. The side effect profile is significantly different compared to cathing a slightly older, more mature baby. So this field is evolving. We still don't have a trial in the smallest babies. Early on, the effects of cath closure early on. So I think that would be an important thing to keep an eye out for. I know in the US, cath closure has gone up dramatically. So I'm sure in the next little bit, there'll be more observational studies coming out on how it is impacting clinical care in these institutions.

Ben Courchia MD (10:28.558) From a pharmacological standpoint though, I think that there is an argument to be made about how we've been in this uncertainty for many, many years, and we've had these three drugs that we all know about: indomethacin, ibuprofen, and acetaminophen. And it seems like year over year we're losing one of them. Initially, indomethacin fell out of favor. Now, ibuprofen has a lot of concerns associated with it, and it seems like we're just left with acetaminophen. Do you think there is still a way for us to understand the physiology better so that we can continue to resort to these medications, or what do you think the future will look like then?

Souvik Mitra MD (11:07.106) As I said in my presentation as well, all drugs are bad. But some are useful sometimes. So we need to find out the right patient population. If you start using these drugs indiscriminately, based on loose criteria, then overall, you'll end up seeing more harm, as these large pragmatic trials are showing. So we need to be more selective. Choosing the medication is secondary. The primary thing is which patients you want to expose these medications to.

Ben Courchia MD (11:45.038) I think that's a great point, and I believe that we're learning specifically in the past few years that the babies who require interventions are getting very different. It looks like today, the question of the PDA is very compelling for babies that are born 26 weeks or below.

Souvik Mitra MD (12:03.456) Exactly.

Ben Courchia MD (12:04.16) And it didn't used to be like that, right? I think that in the past we were probably looking at 30 weeks or below. But today, nobody is really struggling with a PDA on a 29-weeker. But now 26 and below is that population that is needing attention. And it's not the population that was studied back in the day.

Souvik Mitra MD (12:19.93) Exactly. If you look at the trials, these babies are much less represented in these trials. Of course. So we don't really have that data, and that does not put a lot of confidence among clinicians. So we looked at data from the US and also Canada, where in the older preterm babies, more than 26 weeks, 26 to 28 weeks, people are following the evidence. So PDA diagnosis has gone up, but PDA treatment rates have gone down. But in the less than 26-weekers, PDA diagnosis rates have gone up. So have the treatment rates. So why are people deviating from evidence? They feel something is different from the trials compared to the baby that they're caring for.

Ben Courchia MD (13:04.302) Yeah, and I think that's where these babies are so interesting and complex at the same time. We're talking about a 22-weeker, and at two weeks of age, they're corrected to 24 weeks. A 26-weeker at two weeks of age is 28 weeks corrected. And they are different patients, so different. And for a baby that reaches 28 weeks, I feel like, okay, we're almost at the point of maybe getting a little bit of stability. But when you're 22 and you're now 24, you're in the throes of prematurity and survival is a big question. So it's very interesting to see that this patient population has very interesting needs both based on their original gestational age and their evolution through their course. So it's always very difficult when the AAP comes out and makes a clinical report. Do you think they're going to eventually come back on this and clarify?

Daphna Yasova Barbeau MD (13:56.066) Yeah, people may not know.

Ben Courchia MD (13:57.166) We assume that everybody knows who you are, but you practice in Canada, right? So obviously the CPS, the Canadian Paediatric Society, is the equivalent of the AAP over there, but the AAP statement is a very American problem because it affects the people practicing in the US. So I'm asking your opinion obviously as a Canadian looking at this from the outside.

Souvik Mitra MD (14:19.682) I think what will happen is that there will be more observational reports of the impact of the statement on clinical practice. Exactly, exactly. And that might lead to modifications or clarifications. You cannot label...

Daphna Yasova Barbeau MD (14:30.454) What we're having to do with probiotics now.

Souvik Mitra MD (14:43.434) all preterms and put all preterms in one box. And that is probably causing a lot of concern and confusion amongst practitioners, so that might need some clarification. Say, for example, in our center, we follow a selective early treatment strategy. We have had one cath closure in the last year. We're a 60-bed level four center. Our treatment rates are down overall. If you talk to someone who is just reading the evidence, they would say that, well, if you're screening early, you must be treating way more. But again, that is not the case. What we are doing is watchfully waiting in a lot of babies, not willfully ignoring the shunts.

Daphna Yasova Barbeau MD (15:39.114) I like that. We also have a very American problem of now, once a statement is out, it's going to be very hard for people to treat, even if they wanted to, even if they intended to.

Ben Courchia MD (15:50.766) Even though the AAP has had a reputation obviously to be able to adjust based on the evidence, I'm more hopeful with this particular issue than I am with the probiotics. The FDA is going to be much harder to move on a statement than the AAP.

Souvik Mitra MD (16:05.664) Yes, simple example. People are quoting the NRN PDA trial as the reason why we should be moving away completely from PDA treatment. If you have a 23-weeker on high frequency, day three of life, 60% oxygen, has a PDA, you do an echo, PDA size of 1.6 left to right, that baby was not even in the trial because that baby was excluded due to a lack of echo. Those little details don't come out, yeah, they don't come out on the AI-generated summaries that tell people to stop treating PDAs. So those are the nuances that we need to ask clinicians, we need to understand the limitations of the evidence when we have such a small baby in front of us.

Ben Courchia MD (16:50.208) It is an opportunity for us as clinicians to document this. I think that you could potentially treat a PDA and say based on the evidence, based on the fact that this is a patient that meets criteria that would have not been included in those categories, I feel that I could treat. You could still act in good conscience with these infants. So I think that's something that people should be reminded of.

Daphna Yasova Barbeau MD (17:09.198) My question to you is, you've told us a little bit that you're selecting for specific babies in this smallest group, earliest group. So which is the right baby?

Souvik Mitra MD (17:20.75) So there are different ways you can approach this, and different institutions have come up with different criteria. We use what we call the SMART-PDA criteria, which is based on the trial that we just completed, where we categorize babies into mild, moderate, and severe clinical, and mild, moderate, and severe echocardiographic criteria. And we only treat babies who have at least moderate clinical with moderate echo criteria, or severe echo regardless of clinical. So even babies who have moderate echocardiographic criteria and they're very stable, we won't treat those babies. Now, the funny thing is that those babies whom we don't treat, had they been randomized to the treatment arm of the BeNeDuctus or the Baby-OSCAR trials, they would have received ibuprofen. So no wonder when you put all of that together you're seeing harm because a lot of those babies with small shunts are getting exposed to medication they didn't need to get exposed to. So that is the selection that we are trying to bring in. At least locally, we are seeing some success with that. Obviously we'll have to follow our patient cohorts for a much longer period, but definitely, as I said, the treatment rates overall are actually down.

Ben Courchia MD (18:46.062) When can we expect the results of this SMART-PDA to come out?

Souvik Mitra MD (18:50.446) It's under review, fingers crossed. So hopefully sometime this year.

Ben Courchia MD (18:55.124) Okay, very nice. Congratulations, Souvik, and thank you for dropping by the booth.