REVIEWED BY

Rebeca Cavazos, MD, FAAP
Baylor College of Medicine/Texas Children’s Hospital

Gautham Suresh, MD, DM, FAAP
Baylor College of Medicine/Texas Children’s Hospital

MANUSCRIPT CITATION

Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Fernandez E, Sankar M, Leone T, Perez J, Serize A, and the PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators. PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age. J Pediatr 2018; 205:41-48.e6. PMID: 30340932.

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) In neonates less than 28 weeks gestational age with moderate to large patent ductus arteriosus (PDA) after the first week of life, (I) does early routine pharmacologic treatment (C) compared to conservative management with prespecified rescue treatment criteria (O) decrease the need for ligation or the presence of PDA (T) at discharge?

METHODS

• Design: Prospective, multicenter exploratory randomized controlled trial
• Allocation: Concealed, 1:1 ratio
• Blinding: Unblinded; infants in the conservative treatment arm did not receive placebo intravenous infusion
• Follow-up period: Until hospital discharge
• Setting: Seventeen international sites after obtaining IRB approval at each site between January 2014 and June 2017
• Patients:
  • Included: Infants who met all 3 of the following criteria:
    • (1) age 6-14 days if delivered between 23 and 25 ^6/7 weeks or 8-14 days if delivered between 26 and 27 ^6/7 weeks
    • (2) Moderate-to-large PDA
      • Defined as:
        • Internal ductus ≥1.5mm (or a PDA:left pulmonary artery diameter ≥ 0.5), and one or more of the following echocardiographic criteria: (1) Left atrium to aortic root ratio ≥ 1.6, (2) ductus flow velocity ≤ 2.5 m/second or mean pressure gradient across the ductus ≤ 8mmHg, (3) left pulmonary artery diastolic flow velocity >0.2 m/second and/or (4) reversed diastolic flow in the descending aorta.
      • (3) receiving greater than minimal respiratory support which included any support of or higher than high flow nasal cannula with flow rate >2L/minute and fraction of inspired oxygen greater than 0.25.
    • Excluded:
      • Previous treatment with indomethacin or ibuprofen
      • Chromosomal anomalies
      • Congenital or acquired gastrointestinal anomaly
      • Previous episode of necrotizing enterocolitis (NEC) or intestinal perforation
      • Active pulmonary hemorrhage at enrollment
      • Contraindications to the use of indomethacin or ibuprofen such as recent receipt of hydrocortisone (previous 24 hours), low urine output (<1 mL/kg/hr in previous 8 hours), high serum creatinine (>1.6 mg/dL), low platelet count (<50,000/mm³), or abnormal coagulation studies. Sixteen of the seventeen centers also excluded infants receiving inotropic support for hypotension at the time of enrollment
    • Intervention: Infants with moderate to large PDA present after the first week of life and randomized to the early routine treatment (ERT) group were treated with either indomethacin, ibuprofen, or acetaminophen with indomethacin backup if the PDA failed to constrict after the initial treatment. Infants randomized to the conservative treatment (CT) group did not receive any medications to close the PDA or placebo infusion. Both groups of infants received repeat echocardiograms 7-10 days after randomization and every 7-14 days thereafter if the PDA remained moderate to large until PDA closure or hospital discharge. Pre-specified criteria for rescue treatment in the conservative treatment group were a persistent moderate-to-large PDA with one or more of the following: (1) inotrope-dependent hypotension that required continuous dopamine support for at least 3 days (with no obvious cause, other than the moderate PDA, to explain the condition), with hypotension defined as mean blood pressure at least 2-3 mmHg below the infant’s postmenstrual age; (2) oliguria that persisted for at least 2 days with no obvious cause, other than the moderate PDA, to explain the condition; (3) requirement for gavage feedings beyond 35 weeks postmenstrual age owing to increased work of breathing; and (4) requirement for significant respiratory support, defined as exceeding of specified thresholds of respiratory support at different postnatal ages.
    • Outcomes:
      • Primary outcome: Ligation of PDA or need for PDA cardiology follow-up at discharge
      • Secondary outcomes: Duration of intubation and respiratory support, need for diuretics, time to full enteral feeds, duration of gavage feeding, average daily weight gain, incidence of persistent moderate-to-large PDA shunt at 10 days after enrollment, incidence of rescue treatment eligibility criteria met, incidence of rescue treatment recieved, and incidence of serious neonatal morbidities such as necrotizing enterocolitis, bronchopulmonary dysplasia (BPD), death, and BPD/death before 36 weeks post-menstrual age.
    • Analysis and Sample Size:
      • The sample size (100 patients in each arm of the trial) was calculated based on an anticipated increase in the outcome of ’need for PDA ligation or need for cardiology follow-up for PDA after discharge’ from 41% in the early routine treatment group to 62% in the conservative treatment group. The alpha and beta used in the sample size calculation were not described.
      • An intention-to-treat analysis was performed
    • Patient follow-up: % included in analysis
      • 1,788 babies screened
        • 10% died prior to enrollment
        • 41% saw ductal constriction before enrollment period
        • 1% required insufficient respiratory support to enter the study
      • 48% eligible infants
        • 24% of eligible infants enrolled due to exclusion criteria, parental refusal, investigator or parental unavailability, or physician’s decision to manage PDA outside of the study (”lack of equipoise”)
      • Final number: 202
      • 100% patient follow up; all patients enrolled were included in analysis

MAIN RESULTS

Of the 202 children randomized:

Primary Outcome: There was no significant difference between the groups of ligation or presence of PDA at discharge.

Secondary Outcomes: There was no difference in most prespecified secondary outcomes excepting the trend towards a higher incidence of death (P=.07) in infants in the ERT group, which was not statistically significant. The study also showed the expected lower incidence of moderate-to-large PDA at 1 week after randomization in the ERT group (P<.001) as well as the significantly shorter duration after randomization of presence of PDA in the ERT group (median, 7.5 days [IQR 3-21 days] vs 22 days [IQR 13-43 days]).

The secondary analysis was performed based on stratification of patients by gestational age (≥26 weeks and <26 weeks). This secondary analysis did not have adequate power to show a significant difference between any of the outcomes to P<.05, but the authors stated that 3 outcomes had significant interaction terms to a value of P<.15, all higher in patients ≥26 weeks who received early routine treatment of the PDA:

• Death (P_interaction= .07)
• Non coagulase-negative staphylococcal (CONS) bacteremia (P_interaction=.06)
• Days to achieving full enteral feeding of 120mL/kg/day (P_interaction=.07)

These outcomes did reach a level of statistical significance of P<.05 when analyzed with the intent of looking at the effect of treatment on outcome based on gestational age. In other several exploratory analyses, the study found, in infants less than 26 weeks gestation, a lower rate of dopamine dependent hypotension in the ERT group compared to CT group (P<.05).

CONCLUSION

The authors of this paper conclude that there were no significant differences between the ERT or CT groups in either the primary outcome or their pre-specified secondary outcomes. In subgroup analyses, there was a statistically significant increase in adverse outcomes in infants >26 weeks gestational age in the ERT arm, who took longer to reach feeds, had a higher rate of non-CONS bacteremia, and higher incidence of death than infants undergoing conservative treatment, though this study was not powered for these outcomes. However, in infants <26 weeks gestation, a statistically significant decrease in dopamine treatment was noted.

COMMENTARY

Numerous poor outcomes in premature neonates are attributed to the persistent left-to-right shunt of a PDA, such as pulmonary hemorrhage, bronchopulmonary dysplasia, and death. There is also concern that PDAs cause “systemic steal,” leading to intraventricular hemorrhage (IVH), hypotension, and delay of time to full feeds (1,2). The PDA is particularly problematic in the extremely premature neonate: Clyman et al. showed spontaneous closure at 7 days of life in 98% of those infants born at ≥30 weeks compared to just 13% of infants born at 24 weeks (3). No trial, however, has definitively shown reduced incidence of BPD or death with either prophylactic indomethacin or closure of the PDA regardless of timing (4). Thus, optimal management of the PDA in premature infants has long been a source of controversy among neonatologists.

According to the authors, this study, which they describe as a pilot exploratory trial, had two goals – to evaluate whether there is a difference between presumptive and rescue-based treatment of the PDA on ligation and presence of PDA at discharge, and to obtain data on several secondary outcomes to appropriately power future investigations. This trial addressed the current knowledge gap by focusing solely on infants with moderate-to-large PDAs present after the first week of life and evaluating PDA exposure to assess for long term outcomes throughout hospitalization. There was no statistically significant difference, however, in the primary outcome or in many of the pre-specified secondary outcomes.

The authors note many limitations of their trial, which can make this paper difficult for clinicians to generalize to their populations.  The primary outcome is difficult to apply to clinical practice, as most clinicians are less interested in the presence of PDA as they are in preventing its long-term consequences. The small size of the study and high rate (almost 50%) of rescue treatment in the CT arm could have contributed to the lack of difference in the outcomes of the two groups. Further, the multiple comparisons required for the statistical analysis of groups and subgroups impedes our ability to draw conclusions from the appearance of statistical significance.

What the results of this study do suggest is that clinicians should not feel obligated to automatically treat every PDA. Based on the data presented, a reasonable strategy is to follow the infant’s clinical status, treating when necessary. With this strategy, about 50% of infants with a persistent PDA may avoid exposure to the harms of NSAIDs and ligation by the time of discharge. This study also highlights the need for larger trials to assess the long-term consequences of prolonged PDA exposure in lower gestational age infants. This study also helps inform future trials about specific sub-populations of infants to include, and about required sample sizes.

REFERENCES

1. Clyman RI, Saha S, Jobe A, Oh W. Indomethacin prophylaxis for preterm infants: the impact of two multicentered randomized controlled trials on clinical practice. J Pediatr 2007; 150: 46–50.e2.
2. Patole SK, Kumaran V, Travadi JN, Brooks JM, Doherty D. Does patent ductus arteriosus affect feed tolerance in preterm neonates? Arch Dis Child Fetal Neonatal Ed 2007; 92: F53–F55
3. Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol 2012; 36:123–129
4. Fowlie  PW, Davis  PG, McGuire  W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database of Systematic Reviews 2010; 7: CD000174.