Combination pharmacotherapy for patent ductus arteriosus: Rationale and evidence

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.

Keywords: Acetaminophen; Ductus arteriosus; Ibuprofen; Outcomes; Preterm.

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).

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.