Toward a Rational Approach to Patent Ductus Arteriosus Trials: Selecting the Population of Interest

Abstract

See related article, p 33We read with interest the randomized trial report published by Roze et al (the Targeted by echocardiographic tReatment Of the duCtus Arteriosus in Preterm Infants by Ibuprofen or TRIOCAPI Trial).1Roze J.C. Cambonie G. Le Thuaut A. Debillon T. Ligi I. Gascoin G. et al.Effect of early targeted treatment of ductus arteriosus with ibuprofen on survival without cerebral palsy at 2 years in infants with extreme prematurity: a randomized clinical trial.J Pediatr. 2021; 233: 33-42Abstract Full Text Full Text PDF Scopus (4) Google Scholar This investigative group should be applauded for conducting a multi-institutional randomized trial with over 100 patients in each of the 3 groups. We would also like to express our most sincere condolences to the investigative team regarding the untimely death of the principal investigator, Veronique Gournay, whose pioneering vision for this study in addition to her innovative patent ductus arteriosus (PDA) research should be recognized. See related article, p 33 More than 60 randomized controlled trials of PDA treatment, conducted over 5 decades, have failed to provide compelling evidence to support an optimal management approach. The consequences include clinician uncertainty, variable interpretation of the literature and, in some situations, diagnostic and therapeutic nihilism. Observational studies report a strong association between PDA and adverse neonatal outcomes with a greater exposure to the shunt resulting in a higher rate of comorbidities.2El-Khuffash A. James A.T. Corcoran J.D. Dicker P. Franklin O. Elsayed Y.N. et al.A patent ductus arteriosus severity score predicts chronic lung disease or death before discharge.J Pediatr. 2015; 167 (1354-13561.e2)Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar,3Sehgal A. Paul E. Menahem S. Functional echocardiography in staging for ductal disease severity: role in predicting outcomes.Eur J Pediatr. 2013; 172: 179-184Crossref PubMed Scopus (52) Google Scholar Yet, no clinical trial to date has demonstrated that treating a PDA results in a reduction of those adverse outcomes.3Sehgal A. Paul E. Menahem S. Functional echocardiography in staging for ductal disease severity: role in predicting outcomes.Eur J Pediatr. 2013; 172: 179-184Crossref PubMed Scopus (52) Google Scholar,4Zonnenberg I. de W.K. The definition of a haemodynamic significant duct in randomized controlled trials: a systematic literature review.Acta Paediatr. 2012; 101: 247-251Crossref PubMed Scopus (87) Google Scholar In this volume of The Journal, Roze et al present a prospective randomized trial in which they evaluate PDA status between 6 and 12 hours after birth, specifically distinguishing patients with large PDA vs those with small or closed PDA. The a priori study hypothesis was that “early elimination of a PDA shunt with ibuprofen will improve long-term neurodevelopmental outcomes.” The authors did not identify any meaningful difference in survival without cerebral palsy between infants with large PDA treated with ibuprofen vs placebo before 12 postnatal hours. Interestingly, there were no differences in the primary outcome between infants recruited into the trial and infants assigned to the small ductus group, which raises several questions; most importantly, the adjudication of hemodynamic significance. This study further highlights several challenges encountered in PDA trials. There is increasing recognition that the process to identify infants, most likely to benefit from the elimination of the shunt, is complex; in addition, most trials to-date have failed to consider the variable role of the PDA according to ambient cardiopulmonary physiology. Recent literature suggests that an imprecise approach to adjudication of hemodynamic significance, using PDA diameter alone as a surrogate marker, may result in the selection of the wrong patient.2El-Khuffash A. James A.T. Corcoran J.D. Dicker P. Franklin O. Elsayed Y.N. et al.A patent ductus arteriosus severity score predicts chronic lung disease or death before discharge.J Pediatr. 2015; 167 (1354-13561.e2)Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Within the Roze trial, the similar rate of abnormal outcomes seen in infants categorized as “small ductus” when compared with the intervention and placebo groups alludes to this fact. Misclassification of enrolled subjects into physiologically inappropriate categories, may contribute to misunderstanding of the volume of PDA flow required to distinguish between shunts that would benefit from therapy and those that have the potential to close on their own. We propose a moratorium on “pragmatic” randomized trials that enroll patients based on either PDA diameter alone or imprecise measures such as the left atrium to aortic ratio. Rather we suggest that hemodynamic clinicians, epidemiologists, and trial experts work closely together to design studies that enroll patients with phenotypic risk profiles that represent physiologic states at greatest risk of attributable end-organ morbidities. Another major methodologic concern in the current trial is the high rate of open label treatment in the placebo arm; particularly, when coupled with relatively poor efficacy of the intervention drug to close PDAs in the intervention arm. For example, by day 14 the rate of PDA closure was 54% in the placebo arm, compared with 75% in the intervention arm (with only 64% of ducts achieving spontaneous closure in the small PDA [nonrandomized group]). The study was designed to compare patients where early shunt elimination was achieved with a matched control group with prolonged exposure to ductal shunting, but such physiologic separation simply did not occur. It is not surprising, therefore, that the rates of primary and secondary outcomes were similar between groups. It is important to stress that extrapolation of those findings to suggest the futility of PDA treatment is unfounded. One of the fallacies of prior trials is the interpretation of the lack of efficacy of “treatment” as evidence that the disease “PDA” is not a problem. This concept is flawed when medical therapy is only effective in achieving resolution of the disease state (hemodynamic significance) in one-half of the patients.5Mitra S. Florez I.D. Tamayo M.E. Mbuagbaw L. Vanniyasingam T. Veroniki A.A. et al.Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis.JAMA. 2018; 319: 1221-1238Crossref PubMed Scopus (100) Google Scholar Whether high-volume PDA shunts contribute to important neonatal morbidity may only be addressed by clinical trials that enroll the target patient population, randomize patients to interventions that guarantee therapeutic efficacy, and ensure the control population has sustained exposure to pathologic shunts for a critical duration of time (>7-10 days). The increasing availability of percutaneous device closure, which offers definitive closure with an acceptable safety profile, offers the best opportunity.6Bischoff A.R. Jasani B. Sathanandam S.K. Backes C. Weisz D.E. McNamara P.J. Percutaneous vlosure of patent ductus arteriosus in infants 1.5 kg or less: a meta-analysis.J Pediatr. 2020; (Epub ahead of print)https://doi.org/10.1016/j.jpeds.2020.10.035Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Finally, the validity of the primary outcome as a relevant measure in this context is highly questionable because it underestimates the importance of both modulating neonatal disease and biological plausibility, and instead, places emphasis on a complex outcome with many uncontrolled confounders. The over-reliance on 2-year neurodevelopmental outcome may mask more tangible benefits of early shunt elimination such as chronic lung disease or chronic pulmonary hypertension.7Philip R. Lamba V. Talati A. Sathanandam S. Pulmonary hypertension with prolonged patency of the ductus arteriosus in preterm infants.Children (Basel). 2020; 7: 139Google Scholar The desire to optimize Qp:Qs in patients with deranged hemodynamics secondary to high-volume shunt, remains an important consideration for clinicians. It would be puerile to assume that we can achieve a difference in long-term outcomes, if neonatal morbidities remain unchanged between groups. In addition, some may consider it to be physiologically implausible that an intervention carried out within the first 72 hours after birth would have major ramifications 2 years after the primary exposure. Independent modulator effects of confounding illnesses and therapies during the intervening time period and socioeconomic effects (eg, nutrition, financial status) after discharge may play a substantial role. The biological association between hemodynamic instability in the transitional period and adverse neurologic consequences does have biological merit, however. Trials of prophylactic indomethacin have clearly shown a reduction in severe intraventricular hemorrhage, although neurodevelopmental outcomes remained unchanged.8Schmidt B. Roberts R.S. Fanaroff A. Davis P. Kirpalani H.M. Nwaesei C. et al.Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP).J Pediatr. 2006; 148: 730-734Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar The neuromodulator effect of indomethacin is thought to relate to attenuation of fluctuations in cerebral blood flow. An alternative explanation is that, through modulation of ductal shunt, the increase in preductal cardiac output that occurs as pulmonary vascular resistance falls is attenuated. The relationship between low superior vena caval flow and late intraventricular hemorrhage and the progressive increase in left ventricular output prior to the hemorrhagic insult lends further credence to this hypothesis.9Kluckow M. Evans N. Low superior vena cava flow and intraventricular haemorrhage in preterm infants.Arch Dis Child Fetal Neonatal Ed. 2000; 82: F188-F194Crossref PubMed Google Scholar,10Noori S. McCoy M. Anderson M.P. Ramji F. Seri I. Changes in cardiac function and cerebral blood flow in relation to peri/intraventricular hemorrhage in extremely preterm infants.J Pediatr. 2014; 164: 264-270Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Therefore, if the modulator effect of indomethacin is PDA dependent, universal administration to patients without a high-risk phenotype may expose these patients to the known adverse vasoconstrictor effects of these therapies, thus, diminishing any positive impact on neurodevelopmental outcome. We recommend that future trials should target short-term outcomes, which are biologically relevant and mechanistically plausible, reserving longer term outcomes as a safety assessment measure.11Webbe J.W.H. Duffy J.M.N. Afonso E. Al-Muzaffar I. Brunton G. Greenough A. et al.Core outcomes in neonatology: development of a core outcome set for neonatal research.Arch Dis Child Fetal Neonatal Ed. 2019; 105: 425-431Crossref PubMed Scopus (40) Google Scholar,12Marlow N. Is survival and neurodevelopmental impairment at 2 years of age the gold standard outcome for neonatal studies?.Arch Dis Child Fetal Neonatal. 2015; 100: F82-F84Crossref PubMed Scopus (33) Google Scholar Regarding the current trial, an alternative interpretation may be that early targeted PDA therapy is safe, however, the relationship between PDA shunts and deranged neurophysiology or brain injury requires prospective delineation prior to embarking on further interventional trials. The recent Cochrane Database review of early therapy further highlights the limitations of current study design that fail to consider developmental variance (discordance in myocardial biology and adaptive mechanisms of an infant born at 22 weeks compared with 28 weeks) and pharmacogenomic variance, in addition to the previously highlighted challenges of defining the population of interest.13Mitra S. Scrivens A. von Kursell A.M. Disher T. Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants.Cochrane Database Syst Rev. 2020; 12: CD013278PubMed Google Scholar Clinicians should interpret the conclusions of systematic reviews with caution, especially when there is marked heterogeneity in trial design, risk of intrinsic bias, and the inclusion of studies conducted more than 15 years ago. The concept of “trial expiry” is highly relevant to the contemporary clinical decision-making process. For example, randomized trials published before 1995 were not likely to have included many patients at <24 weeks of gestation and many routine therapies (eg, inhaled nitric oxide, probiotics) and advanced ventilators were not yet available. As the population of interest is most likely to bias toward patients born at <25 weeks of gestation, the clinical relevance of published metanalyses or systematic reviews is questionable. Significant modifications to study design are essential to enable definitive answer to the question “which PDA should be treated, if any.” Patient selection is imperative and requires comprehensive clinical and echocardiography appraisal, coupled with designing a more efficacious treatment approach to ensure infants in the intervention arm achieve early and prompt PDA closure and shunt elimination while open label treatment in the placebo arm should be avoided. The establishment of a centralized imaging core laboratory for study interpretation by expert PDA readers to verify hemodynamic significance prior to randomization may aid the selection of the target patient population. This will ensure a more appropriate comparison between early shunt elimination in the intervention arm and prolonged shunt exposure in the placebo arm. Spontaneous PDA closure in the control arm, which limits exposure to a matter of hours to days, is a major and uncontrollable limitation of trial design. The last 30 years have seen the PDA interventional pendulum change from universal treatment of all patients to avoidance of treatment; such polarization is both biologically implausible and clinically hazardous. It is now incumbent on neonatologists to study patients who have clear evidence of PDA-attributable hemodynamic instability, evaluate the physiologic impact of definitive methods to modulate the PDA shunt with absolute resolution of any hemodynamic disturbance, and finally characterize the downstream effects of shunt elimination on relevant short-term morbidities and their long-term ramifications. Until these conditions are met, we run the risk of repeating past mistakes and positively contributing to clinical uncertainty, evangelical opinion, and extremes of therapeutic practices. Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical TrialThe Journal of PediatricsVol. 233PreviewTo examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. 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