#410 - [Journal Club] - 📌 Prophylactic Acetaminophen for PDA, Does Early Closure Improve Outcomes?

In this Journal Club episode, Ben and Daphna review the highly anticipated TREOCAPA trial results exploring the prophylactic use of acetaminophen for PDA closure in extremely preterm infants. They break down the study's tailored dosing regimens, safety outcomes like cholestasis, and discuss why achieving a higher rate of early ductal closure didn't necessarily translate to improved survival without severe morbidity. Plus, they share a nod to recent Neo Conference interviews and the realities of conducting clinical research in private practice. Tune in for a nuanced discussion on individualizing PDA management in the NICU!

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Prophylactic Treatment of Patent Ductus Arteriosus With Acetaminophen: A Randomized Clinical Trial. Rozé JC, Cambonie G, Flamant C, Patkaï J, Mühlbacher T, Gascoin G, Rideau Batista Novais A, Tauzin M, Le Duc K, Beuchée A, Joye S, Babacheva E, Bouissou A, Ligi I, Tammela O, Plourde M, Dempsey E, Tosello B, Nguyen K, Vincent M, Andresson P, Binder C, Kruse C, Barcos Munoz F, Kuhn P, Proença E, Bartocci M, Kermorvant-Duchemin E, Nellis G, Lumia M, Giapros V, Rigo V, Sankilampi U, Mendes da Graça A, Rønnestad A, Soukka H, Mondì V, Aikio O, Torre-Monmany N, Rüegger C, Baud O, Zeitlin J, Morgan AS, Baruteau AE, Ancel PY, Carbajal R, Bouazza N, Diallo A, Levoyer L, Kemper R, Hallman M, Alberti C, Ursino M; TREOCAPA Study Group.JAMA Pediatr. 2026 Feb 16:e256150. doi: 10.1001/jamapediatrics.2025.6150. Online ahead of print.PMID: 41697673

Transcript

Ben Courchia MD (00:00.856) Hello everybody, welcome back to the incubator podcast. We're back today for an episode of journal club.

Daphna Yasova Barbeau MD (00:06.544) Good morning. I'm in my post-call snuggly here.

Ben Courchia MD (00:11.212) That's okay. The journals need to be read even when post-call. That's right, you're post-call. I forgot about that. Sorry. That's why you were asking for a late start this morning. I forgot you were post-call. You should have said that.

Daphna Yasova Barbeau MD (00:23.106) Yeah, but you keep us on such a strict schedule.

Ben Courchia MD (00:27.405) Mm-hmm.

Daphna Yasova Barbeau MD (00:30.232) And here we are. We made it. We make it work.

Ben Courchia MD (00:31.458) And here we are. Okay. We're going to start Journal Club. We have a bunch of very interesting articles that we can review. Is there anything that we need to announce? I don't really have any announcements, to be honest with you. We're going to soon go to the Cool Topics in Neonatology conference from the

Daphna Yasova Barbeau MD (00:43.824) for

Ben Courchia MD (01:00.376) California Association of Neonatologists, which will be a lot of fun. And then we'll be at PAS in April. We'll be the official podcast partner of PAS this year. Very excited about that. What else can I say?

Daphna Yasova Barbeau MD (01:04.623) Mm-hmm.

Daphna Yasova Barbeau MD (01:14.778) We've been doing a lot of traveling. I guess maybe to remind people if they haven't checked out our coverage from Neo Conference.

Ben Courchia MD (01:22.924) Yeah, the coverage from Neo Conference is on YouTube, on the main podcast channel, and we've had lots of very interesting interviews with lots of people. Did I have a favorite interview? I would say Mark Mercurio was my favorite interview for sure. I'm biased.

Daphna Yasova Barbeau MD (01:31.344) Mm-hmm.

Daphna Yasova Barbeau MD (01:35.204) Did you have a favorite interview?

Daphna Yasova Barbeau MD (01:41.378) Mm. Yeah, we've been really looking forward to having him on. I love chatting with Souvik Mitra.

Ben Courchia MD (01:50.348) Yeah, Souvik is always a good customer in these areas. But I also found that we spoke to a lot of people from Pediatrix, the company, which was very interesting to get the perspective of clinical neonatologists in private practice. And not just clinical neonatologists in private practice, but clinical neonatologists in private practice who are trying to do more than just clinical care, which is very hard to do. It's very hard to do. It's not like...

Daphna Yasova Barbeau MD (01:53.678) Yeah, and Ariel Salas, those were my top two.

Daphna Yasova Barbeau MD (02:13.434) Yeah. Yeah. Yeah.

Ben Courchia MD (02:17.582) Because I think that one of the things that we've talked about, I hope it comes across in...

Daphna Yasova Barbeau MD (02:19.83) Additionally, there are plenty of our colleagues in academia who are full-time clinical, right? And still trying to squeeze things into their FTE outside of that clinical work.

Ben Courchia MD (02:28.46) Yeah, absolutely. I hope that we've done this well to show that it's not easy to be in private practice and try to do more things, right? To do clinical research, to do quality improvement, to do education. It was interesting to hear from people who have been successful at doing it, how they've done it, and what they've leveraged. Because I think this is the reality for a lot of people. If you are an NIH-funded academic institution provider, good for you. You've reached the pinnacle of how to have your time protected.

Daphna Yasova Barbeau MD (03:12.112) But I think it was such a good reminder that so many institutions want to be engaged in research, and you may be neighbors to an academic center. When we talk about multi-site studies, sometimes it's people in your own community that we can be collaborating with. They're seeing a lot of babies every day, and hospitals want to be engaged; clinicians want to be engaged in research.

Ben Courchia MD (03:25.422) Totally.

Daphna Yasova Barbeau MD (03:41.968) So I think we have such a broader pool of colleagues and babies to be studied than we think.

Ben Courchia MD (03:54.146) Yeah, absolutely. But without further ado, I guess we can get into Journal Club?

Daphna Yasova Barbeau MD (04:02.705) It's time.

Ben Courchia MD (04:04.012) So I guess per tradition, I'm going to open the show today. You mentioned Souvik, so I was like, maybe this is going to be the right way to start this particular episode. And we're going to talk about the PDA. I will tell you about that in a second, because clearly we're not done.

Daphna Yasova Barbeau MD (04:18.733) Alright. Oof. I thought we were done talking about the PDA.

Daphna Yasova Barbeau MD (04:28.227) Okay.

Ben Courchia MD (04:30.376) This article that I am reviewing today is called Prophylactic Treatment of Patent Ductus Arteriosus with Acetaminophen. It was published by first author Jean-Christophe Roze from France, who we're actively trying to get on the French podcast. The bottom line is that this is the result of the TREOCAPA study group, which if you were listening to Souvik Mitra's interview, he mentions the results. Now the problem that you run into, that's not something that I've seen being part of hemodynamics, is that people are very collaborative. So these guys have the results of some of these trials ahead of schedule. I've seen the results of the TREOCAPA trial a little bit early myself, but...

Daphna Yasova Barbeau MD (05:10.201) Yeah.

Daphna Yasova Barbeau MD (05:14.545) Look who's in the know now.

Ben Courchia MD (05:16.972) I was so surprised somebody brought them up at a private meeting, and I was like, very interesting. Anyway, the background is terrifying, right? When you read about this, I'm going to read the first sentence because I read it, paused, and you're going to see why. "Management of the PDA in extremely preterm infants remains a matter of debate, even though pharmacological constriction and closure of the ductus have been recognized for 50 years." And then I was like, five-zero. We've been at this for 50 years. "Experimental evidence and clinical cohort studies confirmed the association of the development of a symptomatic PDA with mortality and morbidity." "In contrast, meta-analyses and recent randomized controlled trials show..."

Daphna Yasova Barbeau MD (05:48.897) Yeah, I know. That's as old as neonatology.

Ben Courchia MD (06:08.6) "...that the prophylactic or early targeted treatment of a pre-symptomatic PDA by indomethacin or ibuprofen does not improve outcome, nor is expectant management inferior to early targeted ibuprofen treatment." "These observations could be related to the numerous adverse effects associated with these drugs." This is the other part of the history that got me. "Acetaminophen appeared as a new potential therapy in this debate since 2011." My God, it's been like 15 years. "Although its action on the constriction of the ductus arteriosus has been known since 1981."

Daphna Yasova Barbeau MD (06:46.607) Hmm.

Ben Courchia MD (06:47.983) Man, it's just kind of like, jeez.

Daphna Yasova Barbeau MD (06:51.033) But it's interesting, because for pretty much our entire careers, acetaminophen has been on the landscape and on the rise. But it was basically just when we started. Yeah.

Ben Courchia MD (07:02.508) Yeah, kind of, right? Mechanistically, they mentioned that it's postulated to inhibit the peroxidase enzyme, and this inhibition results in the downregulation of prostaglandin H2 synthase, which consequently decreases the production of prostaglandin E2, ultimately helping the closure of the ductus. Despite its promise, the authors have identified a few critical research gaps. First, the efficacy and safety of acetaminophen, specifically in extremely preterm infants, needed a closer look as these tiny babies were only included in a very small number in previous trials. Something that Souvik has mentioned on our interview is that obviously as we're resuscitating more 22, 23-weekers, these trials that were not including them suddenly now have to be revisited. Second, the optimal dose and duration of treatment to effectively constrict the ductus are unknown, meaning the pharmacokinetics and pharmacodynamics needed to be established. This is where the TREOCAPA project comes in. To fill these gaps, the trial, which stands for prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen, was a massive phase two and phase three study. The phase two portion of the study used a Bayesian approach to identify the minimum effective dose needed to close the ductus. We're talking about babies who are born at 26 weeks of gestation or less. The trial we're reviewing today represents the phase three of the project. The primary hypothesis of this randomized clinical trial was that prophylactic treatment with an appropriate dose of acetaminophen would increase survival without severe morbidity at a post-menstrual age of 36 weeks. They deliberately chose a prophylactic approach. Their goal was to intervene very early to rapidly reduce the left-to-right shunt, thereby preventing systemic under-circulation and pulmonary overflow. They hoped that this would improve survival without adding serious morbidity. I'm going to walk you through a little bit of the methods. They conducted a multicenter, double-blind, randomized, placebo-controlled superiority clinical trial. The patients were randomized into two arms in a one-to-one ratio. It took place in 43 neonatal intensive care units across 14 European countries. Enrollment ran from October 2020 to April 2024.

Ben Courchia MD (09:25.388) Mentioning the phase two preceding the phase three trial, we're focusing on babies between 23 and 26 weeks of gestation. The patient population eligible for inclusion were babies whose gestational age at birth was between 23 weeks and zero days to 28 weeks and six days inclusive, and if their postnatal age was 12 hours or less. They had comprehensive exclusion criteria. They excluded babies who had congenital anomalies, severe twin-to-twin transfusion, or suspected pulmonary hypoplasia. They also excluded infants with hepatic impairment, which was suspected if there was a hemorrhagic syndrome or severe hypoxemia. Further exclusions included infants who exhibited extreme clinical instability with a high risk of rapid death, if the clinical team failed to start the treatment before 12 hours of life, if the parents were under judicial protection—which was a new exclusion criterion that I had not seen before in most studies—or if the infants were enrolled in another PDA trial. What kind of interventions are we looking at? I think this is where it gets really interesting. Based on the findings of the phase two trial, the intervention dosing was tailored by gestational age. For infants that had a gestational age between 27 and 28 weeks, they began with a 20 milligram per kilogram loading dose within 12 hours of birth, followed by 7.5 milligrams per kilo every six hours for five days, for a total of 20 doses, which is not the usual dose I use, for example. This specific regimen corresponded to the minimum effective dose identified in previous trials for closing the ductus in this particular age bracket. If you were more immature than that, 23 to 26 weeks, the dosage was a bit higher. They received a 25 milligram per kilo loading dose, followed by 10 milligrams per kilo every six hours for five days. I thought that was very interesting.

Ben Courchia MD (11:28.992) You're muted in case you're making any comments. I'm just letting you know. Just for fun.

Daphna Yasova Barbeau MD (11:32.259) Yeah, it's interesting, because probably dose matters. You gotta pick something.

Ben Courchia MD (11:37.23) Yeah. But we usually do... I'm including you in this. We usually do 10 to 15 milligrams per kilo Q6 for a couple of doses, right? That's kind of what I've done before. I haven't done this sort of loading of the acetaminophen. They looked at specific outcomes. The primary outcome of the trial was survival without severe morbidity assessed at 36 weeks post-menstrual age or discharge home if this happened sooner.

Daphna Yasova Barbeau MD (11:43.044) Yeah.

Daphna Yasova Barbeau MD (11:47.737) Mm-hmm. Right?

Ben Courchia MD (12:06.348) Severe morbidity was rigorously defined. It included BPD, specifically according to the 2018 NIH definition. It also included necrotizing enterocolitis, intraventricular hemorrhage grade three or four, and cystic periventricular leukomalacia observed at any time up to 36 weeks. They also had a bunch of exploratory secondary outcomes. They looked at successful rates of closure of the PDA, patients who required backup treatment—like additional courses for PDA treatment—whether they were in the intervention or the control group. To confirm the ductus status, obviously, echo assessment was performed to evaluate that. In terms of the statistical approach, when they did their sample size calculation, they were looking to assess a 10% difference in the primary outcome. By reaching 36 weeks, they were hoping to see survival without morbidity going from 50 to 60 percent. They were hoping that this intervention would allow a 10 percent increase in survival. In terms of results, 778 infants were included in this trial in the modified intention-to-treat analysis. There were 391 infants in the acetaminophen group and 387 infants in the placebo group. The maternal and infant characteristics were not significantly different between the two groups. The overall cohort was quite premature with a median gestational age of 26 weeks and an interquartile range from 25 to 27. In terms of weight, the median weight was 850 grams. Looking at the primary outcome, survival at 36 weeks without severe morbidity was observed in 259 infants in the acetaminophen group compared to 246 in the control group. That meant there was 66.2% survival without severe morbidity in the intervention group with the acetaminophen compared to 63.6% in the control group. The absolute risk difference was a mere 2.7 percentage points, relative risk was 1.04, and a p-value of 0.43, meaning that the difference between these two numbers was not statistically significant.

Ben Courchia MD (14:33.858) The researchers also noted that these primary outcomes results were consistently similar across multiple sub-analyses. They found no significant difference when they looked specifically at infants that were either 23 to 26 weeks compared to babies who were 27 to 28 weeks. The one thing that's important to remember—again, something that we've discussed with Dr. Mitra on the podcast—is that as you look at the number of patients you have in this trial, you clearly see a decay in the number of babies enrolled from 28 weeks to 23 weeks. For example, in the intervention arm of the trial, you have 101 infants at 28 weeks, 90 at 27 weeks, 87 at 26 weeks, and you go all the way down to 23 weeks, and there are only 10 babies at that point. When you're comparing outcomes for babies at 23 weeks to 24 weeks, you're talking about a much lower sample size. You can definitely do a proper assessment of the cohort as a whole, but looking specifically at these gestational ages, we don't know. Let's talk about some secondary analyses. Acetaminophen did what it was mechanistically supposed to do. Day seven after birth, the ductus was considered to be closed on echocardiography in 71.2% of the intervention group. What surprised me was that in the control group, it was reported to be closed as well in 52.2% of the group, which was more than I anticipated. That's right. The relative risk difference was 1.36. This was also very important when they looked at all the gestational age groups.

Daphna Yasova Barbeau MD (16:03.607) Wow. Yeah, that's one of the major arguments against closure, right?

Ben Courchia MD (16:24.718) They found that difference to be consistent across all of them, meaning that you didn't see a difference appear to be wider when you looked at more immature babies. Looking at the need for additional intervention, who required a second course or maybe a first course if you were in the control group? At least one backup treatment to close the ductus was observed in 14% of the intervention group and 21% of the control group. I feel like I always give a second course. I don't know about you, Daphna, but maybe because I'm not using the right dose. With that dosing regimen, only 14% required a repeat dose. Interestingly, despite the much earlier closure of the ductus in the acetaminophen group, there were no statistically significant differences in the ventilatory, hemodynamic, or nutritional support required between the two groups during that first week of life. In terms of safety outcomes, the medication was well tolerated. They saw no difference in the change in liver function. Also, both serious and non-serious adverse events, as well as notable clinical events, were reported at rates that were not significantly different between the treatment and the placebo group. There was, however, one exception, which was cholestasis. It occurred significantly more frequently in the group receiving acetaminophen. It was observed in 6.4% of the intervention arm compared to 2.6% in the placebo group. They have a very nice forest plot for primary components where they looked at NEC, severe cerebral lesions, severe BPD, et cetera. You can clearly see that the error bars basically always cross one. I would say that for NEC, the plot seems to favor an earlier acetaminophen course, and the error bar sort of just thankfully inches through the one line. Otherwise, that is well represented there. The conclusion of the article is that the trial found that prophylactic treatment with acetaminophen did not increase survival without severe morbidity at 36 weeks, despite...

Ben Courchia MD (18:49.134) ...the fact that it was better at closing the PDA. So here we are. I would advise people to go and listen to our interview with Souvik, who mentioned some of these results and talks a little bit about the state of affairs when it comes to where we are at with the PDA.

Daphna Yasova Barbeau MD (18:55.257) So here we are.

Daphna Yasova Barbeau MD (19:09.615) So, what will you do with your next PDA?

Ben Courchia MD (19:17.789) I think I agree with what we discussed with Souvik. I think there should be an individualized approach to the PDA. I think the AAP—again, this is data coming out of Europe—statement about not treating the PDA in the first two weeks really makes it difficult for us to do much unless you have strong reasoning. But I think with hemodynamic assessment, and for babies that are quite immature, 22 to 26 weeks...

Daphna Yasova Barbeau MD (19:21.327) Mm-hmm.

Ben Courchia MD (19:46.614) I think you cannot really leave a PDA open for too long without causing some damage to the heart.

Daphna Yasova Barbeau MD (19:53.871) All right, buddy. Sounds good.

Ben Courchia MD (19:56.782)

Alright everybody, so we'll see you tomorrow for another episode of Journal Club.