Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT06152796 |
Other study ID # |
closure of PDA |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
December 1, 2023 |
Est. completion date |
January 1, 2026 |
Study information
Verified date |
November 2023 |
Source |
Assiut University |
Contact |
Nada Abdelfatah Abdelaal |
Phone |
01023085851 |
Email |
nadaabdelfatah4[@]gmail.com |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
To compare efficacy and safety of paracetamol and ibuprofen for the pharmacological closure
of patent ductus arteriosus (PDA) in preterm infants.
Description:
The ductus arteriosus (DA) is an essential fetal blood vessel that connects the pulmonary
artery to the aorta and serves to shunt blood away from the lungs into the umbilical
placental circulation where gas exchange takes place.At birth, closure of the DA is a
critical event in the transition to the postnatal circulatory pattern. However, there are
situations in which DA closure does not occur or is delayed, resulting in the condition known
as persistent patent DA (PDA) .
After birth, it usually closes within 48 h. A persistently PDA is diagnosed when the DA fails
to close after 72 h.
PDA accounts for 5% to 10% of all congenital heart diseases. However, the incidence surges up
to 60% in preterm infants and is inversely related to gestational age(GA) and birth weight.
The closure of the DA in full-term infants occurs in two steps. Initially, within the first
few hours after birth,increased arterial PaO2 and decreased circulating prostaglandins allow
the smooth muscle media of the ductus to constrict. As a result of the constriction, the
inner muscle wall of the DA develops profound ischemic hypoxia which leads to the formation
of vascular endothelial growth factor, transforming growth factor beta,and other inflammatory
mediators and growth factors that transform the ductus into a non-contractile ligament.
The clinical consequences of PDA are related to the degree of left- to-right shunting through
the PDA, with its associated change in blood flow to the lungs, kidneys, and intestine . This
results in increased pulmonary blood flow and increased incidence of further comorbidities
such as chronic lung disease, intraventricular hemorrhage(IVH), necrotizing enterocolitis
(NEC), and retinopathy.Therefore, closure of the PDA is essential to prevent these
complications and to improve both cardiorespiratory status and survival rate .
Clinical criteria of hemodynamically significant PDA (hs-PDA) are the following:
tachycardia,bounding pulse with wide pulse pressure, hyperdynamic precordium with continuous
murmur on auscultation, hepatomegaly, edema, unexplained metabolic acidosis, failure of
respiratory distress syndrome to improve at 2-7 days, and unexplained CO2 retention in
mechanically ventilated neonates.
Echocardiography has been examined in multiple studies as an objective measure of
hs-PDA.Echocardiographic criteria of hs-PDA are the following: left atrial dilatation (left
atrial: aortic root >1.6), diastolic turbulence (backflow) on Doppler in the pulmonary
artery, internal diameter of duct >1.5 mm, and reverse end diastolic flow in the descending
aorta/mesenteric artery .
Treatment options for hs-PDA include conservative management, pharmacologic interventions,
surgical ligation, and a transcatheter approach to ductal closure. However, a consensus on
PDA management strategies remains elusive. Surgical ligation is usually considered when other
medical treatments have either failed or were contraindicated.
For this purpose, the first-line therapy is medical and nonsteroidal anti-inflammatory drugs
(NSAIDs) are drugs of choice, preventing the conversion of arachidonic acid into
prostaglandins via cyclooxygenase (COX) inhibition, in both the existing isoforms COX-1
(constitutive) and COX-2 (inducible) . Reduction in prostaglandin levels leads to DA muscular
wall constriction through the hypoxia of ductal vasa vasorum and consequent local
angiogenesis, formation of neointimal tissue, and apoptosis. These mechanisms, in conjunction
with platelet recruitment and activation, lead to processes of obstruction and fibrosis and,
as a result, anatomical ductal closure .
Ibuprofen, a non-steroidal anti-inflammatory drug, inhibits both cyclooxygenase-1 and
cyclooxygenase-2, which are enzymes necessary for the conversion of arachidonic acid to
various prostaglandins among them PGE2.Unlike ibuprofen, paracetamol is thought to act on
prostaglandin synthase at the peroxidase region of the enzyme.The role of paracetamol as an
alternative treatment for the closure of hsPDA has gained attention because of the potential
side-effects of cyclooxygenase inhibitors.
Studies comparing oral paracetamol versus oral ibuprofen in PDA closure reported that oral
paracetamol and ibuprofen were similarly effective for the closure of PDA.While,El-Farrash et
al. demonstrated that oral paracetamol is an effective and well-tolerated, first line drug
treatment of PDA that was comparable to ibuprofen in terms of the rate of ductal closure and
even showed decreased LPA, RVSP and LA/Ao ratio.Also,Al-Shaibi et al. documented that oral
paracetamol was between cost-effective and dominant over both oral and IV ibuprofen
formulations.However, another study done by Roofthooft et al.showed disappointing results
with IV paracetamol administration, as PDA closure was reported in only 18% of the patients
with relatively low gestational age.
Regarding the drug safety profile,Oncel et al.and Dang et al.reported that both drugs were
tolerated and deemed safe in terms of renal and liver variables, as well as a lack of
statistically significant difference in major complications(NEC,IVH,bronchopulmonary
dysplasia).However,Balachander et al. Revealed Incidence of AKI is significantly lower with
paracetamol as compared to ibuprofen.Also, Hammerman et al. reported that paracetamol could
offer important therapeutic advantages over NSAIDs (e.g., indomethacin and ibuprofen), as
paracetamol has no peripheral vasoconstrictive effect and can be given to infants with
clinical contraindications to NSAIDs.
The availability of different management options poses a challenge for neonatologists when
making evidence-based management decisions after diagnosing hemodynamically significant PDAs.
The dilemma is whether to use pharmacotherapy at all, and if a decision is made to treat the
PDA medically, what should be the ideal choice of pharmacotherapy.