Combination pharmacotherapy for patent ductus arteriosus: Rationale and evidence arteriosus

Abstract

While cyclooxygenase inhibitors have been the most common medications used to facilitate earlier closure of patent ductus arteriosus in preterm infants, adverse effects and low efficacy in extremely low gestational age neonates (ELGANs) have highlighted a need for alternative options. Combination therapy with acetaminophen and ibuprofen is a novel strategy for PDA treatment in ELGANs, as it may facilitate higher ductal closure rates via additive action on two separate pathways inhibiting prostaglandin production. Initial small observational studies and pilot randomized clinical trials indicate potentially higher efficacy of the combination regime to induce ductal closure in comparison to treatment with ibuprofen alone. In this review, we examine the potential clinical impact of treatment failure in ELGANs with significant PDA, highlight the biological rationale in support of studying combination therapy, and review the randomized and non-randomized studies to date. With the rising number of ELGANs receiving neonatal intensive care, who are vulnerable to PDA-related morbidities, there is an urgent need for adequately powered clinical trials to systematically investigate the efficacy and safety of combination therapy for PDA treatment.

Introduction

In preterm neonates, patent ductus arteriosus (PDA) is associated with impaired lung function, and reduced renal, gastrointestinal and cerebral perfusion,^1–9 as well as higher rates of mortality and major morbidities such as intraventricular hemorrhage, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and acute kidney injury (AKI).^10–14 Management of PDA, the most common cardiovascular disorder of prematurity, is a key component of neonatal intensive care practice.^15–17 Despite decades of research and investigation of several pharmacological agents, the failure rate for monotherapy with cyclooxygenase inhibitors (COXi) or acetaminophen for the first treatment course remains unacceptably high, especially in extremely low gestational age neonates (ELGANs: GA at birth <28 weeks).^18–22 Combination therapy, comprising acetaminophen and ibuprofen, is a novel strategy that may facilitate PDA closure via additive or synergistic action on two separate pathways inhibiting prostaglandin production. In this review, we examine the potential clinical impact of treatment failure in ELGANs with significant PDA, highlight the biological rationale in support of studying a combination treatment regimen and review the efficacy and effectiveness of combination therapy reported in randomized and observational studies.

PDA in ELGANs and current treatments

Among ELGANs, the group at highest risk for PDA-associated morbidities, approximately 60% will experience treatment failure after monotherapy.^20–22 Treatment failure is associated with adverse clinical outcomes among ELGANs, including increased mortality and BPD,^23–27 and is a major barrier in evaluating the clinical impact of PDA treatment. Several meta-analyses have reported that PDA monotherapy confers no demonstrable improvement in neonatal outcomes.^28–30 This has contributed to intensification of the controversy regarding whether “To treat or not to treat a PDA” and been associated with marked variability in PDA treatment practices across the globe. Observational data from centres that adopted a more conservative or selective approach to PDA treatment have indicated worsening clinical outcomes in ELGANs while outcomes for mature preterm infants have largely remained similar across epochs.^31,32 This possibly points towards under-representation of ELGANs in contemporary PDA treatment clinical trials. Although clinical trials have not demonstrated benefit of PDA treatment, morbidity and mortality potentially attributable to a PDA cannot be expected to improve when the treatments studied are inefficacious.

Impact of treatment failure in ELGANs

Ibuprofen, followed by acetaminophen, are the most commonly used monotherapies for first and second PDA treatment courses,^33,34 respectively, among ELGANs. Infants who fail to respond are often given further treatment courses with the same or different agent,^18,19 while symptomatic PDAs unresponsive to medical management may be closed using invasive procedures.³⁵ One key challenge in medical management is the high failure rate of the first treatment course with monotherapy, irrespective of the agent used.^33,36 While pooled data has identified that PDA monotherapy has 67% efficacy for facilitating PDA closure or reduction to insignificant size within 1 week,³⁷ these data represent therapeutic response rates for the relatively mature preterm neonates enrolled in these clinical trials. In contrast, the effectiveness of monotherapy among ELGANs appears significantly lower. In a multi-center retrospective study of 511 preterm infants <29 weeks’ gestation with a significant PDA requiring treatment, 106 infants of 23–24 weeks gestational age (GA) were compared to 405 infants of 25–28 weeks GA.²⁰ The success rates of first cycle of monotherapy for PDA treatment were 31% [ibuprofen: 48% versus acetaminophen: 12%] and 60% [ibuprofen: 63% versus acetaminophen: 52%] for 23–24 weeks GA and 25–28 weeks GA, respectively. The surgical ligation rates and AKI post treatment were significantly higher in the 23–24 weeks GA compared to the 25–28 weeks cohort.20 Khuffash et al.21 conducted a single-center, randomized control pilot study of 60 infants <29 weeks GA with a high PDA severity score (≥5.0) at 36–48 h of age who received either ibuprofen or placebo intravenously (IV). In a post-hoc analysis of this trial, the rates of BPD/death were lower in the intervention success group (29%) when compared to the intervention failure group (85%) or the placebo group (60%).²⁴ Sung et al.²² conducted a randomized, double-blind, placebo-controlled, noninferiority clinical trial on preterm infants 23–30 weeks GA with significant PDA comparing oral ibuprofen versus placebo. Complete ductal closure after one week of the first course of ibuprofen was only achieved in 8% of neonates compared to 2% in the placebo arm for infants born at 23–26 weeks GA.²² The low efficacy of ibuprofen or acetaminophen monotherapy coupled with increased adverse effects in the highest risk patients may be a significant hurdle in investigating effects of PDA intervention on clinical outcomes,²² with authors calling for more effective treatment strategies in future trials.²¹ Combination therapy with acetaminophen and ibuprofen is emerging as a new treatment regime which may result in higher treatment success.³⁸⁻⁴²

Biologic rationale for synergy between ibuprofen and acetaminophen

Although NSAIDs and acetaminophen have functional similarities, they differ in the mechanism of action.^43–45 NSAIDs act on the cyclooxygenase (COX) site of the enzyme prostaglandin H₂ synthetase to reduce prostaglandin production, while acetaminophen is thought to act through the peroxidase (POX) moiety (Fig. 2).^46–48 On the clinical front, the potential for additive action and improved efficacy of combination treatment with ibuprofen and acetaminophen has already been demonstrated in randomized controlled trials (RCTs) in children and adults for disease states whose pathophysiology, similar to PDA, are governed by circulating prostaglandins, (e.g. fever and pain relief). Ong et al. conducted a qualitative systematic review to evaluate the efficacy of the combination of acetaminophen and COXi versus either drug alone in various post-operative acute pain models. In 21 studies including 1909 adult patients, there was >30% reduction in pain intensity and need for analgesic supplementation with combination therapy vs. monotherapy with COXi or acetaminophen, proving the superiority of combination therapy for analgesia.⁴⁹ Wong et al. conducted a systematic review and meta-analysis of 6 RCTs enrolling 915 febrile children to assess the efficacy and side effects of combining acetaminophen and ibuprofen, compared with monotherapy, for treating fever in children. They concluded that combination therapy significantly reduced fever at 1 and 4 h after administration with no serious adverse events compared to monotherapy with either drug.⁵⁰ Additional studies enrolling ELGANs with PDA are necessary to investigate whether similar synergy may increase treatment efficacy and improve clinical outcomes.

Fig. 2 – Mechanism of action (combination therapy).

The arachidonic acid metabolism pathway, depicting the interactions of drugs (inhibitory, such as corticosteroids, NSAIDS, or acetaminophen/paracetamol) and endogenous compounds (stimulating, such as hydrogen peroxide and reactive oxygen species) with the enzymes involved in this pathway that regulate the production of prostaglandins. Reproduced with permission from Weisz DE, Jain A, McNamara PJ. Patent Ductus Arteriosus. Ediciones Journal SA; 2016.

Biological plausibility: pre-clinical experiment

To examine the biological plausibility of a combined benefit from the action of ibuprofen and acetaminophen on ductal tissue, a mouse model of vessel reactivity was employed, using pressure myography to evaluate responses of the ex vivo ductus to either drug or their combination. Studies were conducted at Vanderbilt University Medical Center, using previously published methods,^51,52 in accordance with the National Institutes of Health animal care standards and with approval of the Institutional Animal Care and Use Committee using the isolated ductus arteriosus from late gestation mice. In brief, ductus segments from fetuses on day 19 of pregnancy (the morning of expected night-time delivery) were surgically isolated and mounted on glass pipette tips in custom microvessel perfusion chambers. Myography chambers were placed on inverted microscopes equipped with a digital image capture system (IonOptix, Burlington, VT) to record intraluminal diameter. Mounted vessels were pressurized using a column of Krebs buffer and allowed to equilibrate, after which the pressure was increased to approximate mean arterial pressure (20 mmHg). Vessels were then challenged with two separate exposures to 50 mmol/l KCl in Krebs buffer to confirm reactivity and determine maximum constriction values. After wash-out with Krebs buffer, vessels with proven reactivity were exposed to increasing concentrations of ibuprofen or acetaminophen or both, and changes in lumen diameter were plotted in real-time to determine the concentration-specific effects of each preparation. This experiment identified significantly higher DA constriction (negative %change), at lower individual drug concentrations, with exposure to combination of ibuprofen and acetaminophen vs. either drug alone (p<0.05; Fig. 1), suggesting a combined benefit and potential synergistic effects.^53,54

Fig. 1 – Response of the isolated ductus arteriosus to combination therapy.

Using pressure myography, the isolated ductus arteriosus of late gestation mice (representative pups from 5 different litters) showed limited contractile response to increasing concentrations of either ibuprofen (red) or acetaminophen (blue), in agreement with prior studies (ref. 51,52). In contrast, exposure of the isolated ductus preparation to increasing concentrations of both ibuprofen and acetaminophen (green) showed significant constriction compared to baseline diameter (p<0.05, ANOVA) The combined effects of ibuprofen and acetaminophen were greater than either drug alone (p<0.05, two-way ANOVA), suggesting potential synergism between compounds for ductus constriction. Data shown are mean ± SEM (Graphpad Prism 7.0).

Clinical evidence for combination therapy for PDA treatment

Results from a small number of RCTs and observational studies have provided early evidence of possible improved efficacy of combination treatment and a potential solution to the high treatment failure rates with PDA monotherapy. While a large RCT powered to detect clinically meaningful differences for major neonatal outcomes is lacking, a small number of uncontrolled observational studies and a few small pilot trials exploring combination therapy for PDA treatment have emerged (Table 1).

Table 1 –

Studies evaluating combination pharmacological treatment for PDA among preterm neonates.

Author, Year	Study Design	N	Number of ELGANs	Inclusion criteria	Results	Limitations
Non-randomized studies
Aikio et al. (2020)55	Retrospective cohort:  2002–2018	N = 121  Ibu+Acet: 18  Ibu: 103	NA	Birth GA < 32 weeks and/or birth weight < 1500 g, and PDA	PDA closure rate:  Ibu+Acet: 11/18 (61%)  Ibu:48/103 (47%)	– Small sample size – Historical cohort from 2002 to 2018 – 50% reduction in acetaminophen dose (7.5 mg/kg every 6 h) compared to current contemporary dose of 15 mg/kg every 6 h
Kimani et al. (2020)39	Retrospective cohort:  2012–2017	N = 140  Ibu+Acet:17  Ibu: 22  Indomethacin: 72  Acet: 29	NA	Birth GA < 32 weeks who received treatment for PDA	PDA closure rate:  Ibu+Acet: 7/17 (41%)  Ibu: 7/22 (32%)  Indomethacin: 30/72 (42%)  Acet: 11/29 (38%)	– Small sample size – Lack of standardized approach to confirm treatment success with only 47% having a post treatment echocardiogram to document closure – Lack of standardized objective criteria for hepato-and nephrotoxicity
Shah et al. (2022)41	Prospective cohort study:  2017–2019	N = 31  Ibu+Acet:20  Ibu:11	NA	Neonates < 29 weeks GA, post-natal age ≤ 14 days and birth weight < 1000 g with significant PDA	PDA closure rate:  Ibu+Acet: 11/20 (55%)  Ibu:6/11 (54%)	– Small sample size – Lack of blinding for patients and personnel – Lack of specific protocol to initiate second course of treatment
RCTs
Hochwald et al. (2018)38	Randomized double blinded pilot study  2014–2016	N = 24  Ibu+Acet: 12  Placebo: 12	NA	GA: 24–316/7 at birth with significant PDA	PDA closure rate:  Ibu+Acet: 10/12 (83%)  Ibu+placebo: 5/12 (42%)	– Small sample size – Single center study
Oboodi et al. (2020)40	Multicenter three arm RCT  2016–2017	N = 154  Ibu+Acet: 19  Ibu:68 Acet:67	NA	Preterm infants < 37 weeks GA at birth with significant PDA	PDA closure rate:  Ibu+Acet: 19/19 (100%)  Ibu: 62/68 (91%)  Acet: 58/67 (87%)	– Details of allocation concealment and blinding not specified – Inclusion of mature preterm neonates in all 3 arms

Ibu: ibuprofen; Acet: acetaminophen; PDA: patent ductus arteriosus; GA: gestational age; RCT: randomized controlled trial; NA: Not applicable; ELGANs: Extremely low gestational age neonates.

Evidence from non-randomized studies

Three non-randomized studies^39,41,55 have compared combination and monotherapy for PDA treatment among preterm neonates. In an unadjusted retrospective cohort study, Kimani et al.³⁹ evaluated 140 neonates < 32 weeks GA; 17 received combination therapy and 123 neonates received monotherapy: 22 (17.9%) ibuprofen, 29 (23.6%) acetaminophen, and 72 (58.5%) indomethacin. The PDA closure rates were comparable between the groups, and there were no differences in adverse effects. Limitations of this study included small sample size, lack of standardized approach to confirm treatment success with only 47% having an echocardiogram after completion of treatment to document closure, and lastly, lack of standardized objective criteria for hepato-and nephrotoxicity. Aikio et al.⁵⁵ evaluated a cohort of 121 preterm neonates with significant PDA who received ibuprofen treatment, including 18 neonates who received concomitant intravenous (IV) acetaminophen for pain therapy. The ductal closure rates were 61.1% (11/18) for combination therapy, compared to 46.6% (48/103) for ibuprofen alone. Fewer infants with combination therapy required a repeat treatment and/or ligation than controls receiving ibuprofen (5/18 patients vs. 45/103 patients, p = 0.047) Limitations of this study included small sample size and a historical cohort from 2002 to 2018. In a prospective cohort study, Shah et al.⁴¹ evaluated 31 preterm neonates < 29 weeks GA, post-natal age (PNA) ≤ 14 days and birth weight < 1000 g with significant PDA. Of the enrolled neonates, 20 received combination therapy compared to 11 who received ibuprofen alone. The rates of ductal closure, ligation and adverse effects were similar between the two groups. Finally, in a case series, Yurttutan et al.⁴² reported 12 preterm neonates (GA: 26–36 weeks) with PNA (15–32 days) with significant PDA resistant to 2 cycles of monotherapy (ibuprofen/acetaminophen). Nine of the 12 neonates (75%) had successful ductal closure. Of interest, the duration of acetaminophen treatment was 5 days in this case series.

Evidence from RCTs

Two RCTs^38,40 have been conducted comparing combination therapy to ibuprofen+placebo/no intervention for PDA treatment in preterm neonates. Hochwald et al.³⁸ conducted a randomized double blinded pilot trial in 24 preterm neonates: 12 randomized to ibuprofen+acetaminophen and 12 to ibuprofen+placebo. Neonates randomized to combination treatment had higher PDA closure rates compared with ibuprofen monotherapy (83% vs. 42%, p = 0.08). Oboodi et al.⁴⁰ conducted a three arm RCT comparing ibuprofen (n = 68), acetaminophen (n = 67) and ibuprofen+acetaminophen (n = 19) in preterm neonates with significant PDA. The closure rate after one and two courses between the 3 groups were similar and the adverse effect profile (AKI, hepatotoxicity, bilirubin levels and platelet count) were comparable between the three groups. The limitation of this trial was inclusion of mature preterm neonates where the likelihood of spontaneous closure of the ductus is high (Table 1). The pooled analysis from RCTs for key outcomes is described in Table 2. Quality assessment of included non-randomized studies and RCTs via ROB-INS-1 and Cochrane risk of bias tool, respectively, as described in (Table in supplemental appendix).

Table 2 –

Pooled analysis from RCTs.

Outcomes	N	Number of studies	Pooled Relative Risk (RR) and 95% Confidence interval (CI)	Heterogeneity (I2)	Certainty of Evidence (GRADE)
PDA open after one course	111	2	0.77 [0.43,1.36]	0	Low
PDA open after two courses	111	2	0.28 [0.08, 0.99]	0	Low
BPD at 36 weeks	24	1	0.80 [0.28, 2.27]	NA	Very Low
NEC	24	1	0.33 [0.01, 7.45]	NA	Very Low
Oliguria	24	1	0.50 [0.05, 4.81]	NA	Very Low

PDA: patent ductus arteriosus; BPD: bronchopulmonary dysplasia, NEC: necrotizing enterocolitis; NA: Not applicable.

Hammerman et al. recently published a systematic review and meta-analysis of 5 studies (2 RCTs and 3 cohort studies) comparing combination therapy versus monotherapy for PDA treatment in preterm infants. They concluded that combination therapy may be more effective than monotherapy with regards to ductal closure. Limitations of this review included integration of RCTs and cohort studies in meta-analysis to derive the conclusion of possible superiority and use of fixed effects model for synthesis when significant clinical heterogeneity in terms of patient population and dose of acetaminophen exists between all included studies.⁵⁶

Ongoing trials

There are two ongoing clinical trials (NCT03648437, NCT05340582)^57,58 comparing combination therapy to monotherapy in preterm neonates with significant PDA. NCT03648437⁵⁷ is a multicenter, randomized, placebo-controlled, double-blind, clinical trial comparing ibuprofen/indomethacin + acetaminophen to ibuprofen/indomethacin + placebo with the aim to recruit 60 preterm neonates with significant PDA across 3 neonatal units. The primary outcome is the rate of ductal closure, and key secondary outcomes include the need for additional therapy for PDA, adverse effects, moderate-severe BPD, severe IVH, moderate to severe NEC, and ROP requiring therapy. NCT05340582⁵⁸ is a pragmatic, multicenter, double-blinded, placebo controlled, parallel, two-armed, superiority randomized trial comparing two treatment regimens (ibuprofen + acetaminophen versus ibuprofen + placebo) for the first treatment course of significant PDA in 310 ELGANs. The primary outcome is a composite outcome of pre-discharge mortality or moderate-severe BPD, and key secondary outcomes include the rate of ductal closure, nephro- and hepato-toxicity, need for additional therapy for PDA, and procedure for PDA closure. These 2 RCTs will help evaluate the efficacy and safety profile of combination therapy for PDA treatment in preterm neonates and inform clinical decisions for PDA management in future.

Conclusions

The current approach to treatment of a PDA in ELGANs is fraught with poor efficacy of monotherapy with nonselective COX inhibitors or acetaminophen in this fragile population. Combination therapy (ibuprofen + acetaminophen) is a novel strategy with a strong biological rationale supported by early evidence of safety and feasibility. However, the current evidence from non-randomized studies and RCTs is in its infancy and inconclusive on account of very small sample sizes, under-representation of ELGANs, varying dosages and duration of acetaminophen therapy and limited information on toxicity of drug combinations. With increasing survival of ELGANs, there is an urgent need for adequately powered, well-designed RCTs specifically for this population to establish the efficacy, safety and impact on major neonatal outcomes of combination therapy for PDA treatment.