Oral Versus Intravenous Medications for Treatment of Patent Ductus Arteriosus in Preterm Neonates: A Cost-Saving Initiative

Abstract

OBJECTIVE

The purpose of the study was to quantify cost savings after promoting oral pharmacotherapy for the treatment of hemodynamically significant patent ductus arteriosus (hsPDA).

METHODS

This was a retrospective before-and-after time series quality improvement study. Oral ibuprofen and acetaminophen use criteria were developed and recommended, rather than the more costly intravenous equivalents. There were 24-month medication use reports generated for both the pre-criteria (Era-1) and the post-criteria (Era-2) implementation phases to identify neonates prescribed hsPDA medications in order to assess cost differences.

RESULTS

Era-1 had 190 treatment courses in 110 neonates for a total medication cost of $171,260.70. Era-2 had 210 courses in 109 patients for a total medication cost of $47,461.49, yielding savings of $123,799.21 ($61,899.61 annually) after criteria implementation. The reduction in intravenous ibuprofen use in Era-2 accounted for all the savings.

CONCLUSION

Preferentially prescribing lower-cost oral medications to treat hsPDA led to significant cost savings.

Introduction

Patent ductus arteriosus (PDA) is diagnosed frequently in premature neonates, with a reported incidence of 38% in very low birth weight (<1500 g)^1,2 and 70% in extremely low birth weight (<1000 g)^1,3,4 neonates. Various treatment approaches have been described in the literature for the management of hemodynamically significant PDA (hsPDA) in preterm neonates. One option includes the conservative strategy of “watch and wait,” with or without fluid restriction.^5–8 A PDA has been reported to close spontaneously (without pharmacologic or surgical treatment) in 94% of neonates born >1000 g⁹ and in 78% of neonates born >28 weeks gestational age.³ The probability of spontaneous closure in smaller, less mature neonates is lower. Ascertaining the degree of spontaneous closure in extremely low birth weight neonates is challenging because up to 70% receive early treatment for their PDA.¹⁰ Controversy exists as to whether a PDA should be afforded the opportunity to close spontaneously over time, or whether a more aggressive approach to treatment should be taken. Proponents of attempts at earlier closure point to un-toward effects of persistently patent left-to-right shunting from the aorta to the pulmonary arteries that cause “ductal steal” of blood from the systemic to pulmonary circulation. The end result of this diversion may lead to systemic hypotension,^11,12 left ventricular insufficiency,¹² pulmonary hemorrhage,^13,14 pulmonary edema,¹⁵ bronchopulmonary dysplasia,^11,16,17 periventricular leukomalacia,¹⁸ intraventricular hemorrhage,¹⁹ oliguria and renal failure,¹¹ necrotizing enterocolitis,^20–22 and death.^21,23–25

More aggressive strategies include pharmacologic management and surgical closure. These approaches may close a greater proportion of PDAs or may close PDAs sooner than waiting for spontaneous closure, but there is no definitive evidence that earlier closure results in improved long-term outcomes.^5,21 There is an emerging body of evidence suggesting less aggressive strategies for PDA management result in outcomes of equal efficacy, and perhaps even lower rates of adverse events.^{4,6,8,26–31} Furthermore, the pharmacologic or surgical treatment for PDA is not benign. First-line medications potentially lead to renal,³² gastrointestinal,³³ and cerebrovascular³⁴ adverse events. Postoperative complications include hemodynamic deterioration,^35,36 respiratory compromise,^36,37 and left vocal cord paralysis,^38–40 and higher rates of bronchopulmonary dysplasia,^{4,26,37,41,42} necrotizing enterocolitis,^27,42 severe retinopathy of prematurity,⁴¹ intraventricular hemorrhage,⁴² and impaired neurodevelopment.^4,42,43 More recent evidence points to better outcomes in infants at highest risk of persistent hsPDAs and in those treated later^21,44–46; however, determining which infants fit these categories has not been agreed upon, and treatment decisions are often made based on clinical, radiographic, echocardiographic, and biomarker criteria.^{12,33,47–52}

Historically, when the decision was made to treat a PDA with medication, indomethacin was considered the drug of choice, but it fell out of favor because of previously described adverse effects.^53,54 Another cyclooxygenase inhibitor, ibuprofen (IBU) lysine, replaced indomethacin as the preferred agent because of its more favorable adverse effect profile and comparable efficacy.^32,54,55 Acetaminophen (paracetamol, or APAP), a prostaglandin synthase inhibitor, has been studied as an alternative medication to the cyclooxygenase inhibitors for the treatment of hsPDA because of its mechanism of action and proposed safer side effect profile (e.g., lower incidence of hyperbilirubinemia and gastrointestinal bleeding), although there are inherent concerns for potential hepatotoxicity along with an absence of long-term safety data.⁵⁶ Acetaminophen has been used as initial management,^57–62 or as secondary management in patients who have contraindications to or failed IBU treatment.^63–70 Literature available at the time of study initiation suggested non-inferiority of APAP compared with IBU for the pharmacologic management of hsPDA.^57,60 Case series of oral^59,63,71 and IV^58,72 APAP demonstrated equal efficacy for ductal closure. The PDA closure rates were also similar to those for oral and IV IBU.^73–78 Since then, other single-center studies and meta-analyses have confirmed the non-inferiority of APAP compared with IBU,^{54,62,79–87} oral APAP compared with IV APAP,⁸⁸ and oral IBU compared with IV IBU^54,89 in rates of ductal closure.

Cost differences between IV IBU and IV APAP and their respective oral dosage forms were substantial during the study period. The purpose of this quality improvement study was to quantify the cost savings realized after adopting medication use criteria promoting the use of oral pharmacologic agents for the treatment of hsPDA.

Materials and Methods

This was a retrospective before-and-after time series quality improvement study conducted at Joe DiMaggio Children's Hospital, part of the Memorial Healthcare System in Hollywood, FL, which is a regional referral center that includes an 84-bed level III NICU. Hemodynamically significant PDA was defined based on clinical, radiographic, echocardiographic, and biomarker findings (Table 1), but parameters were not defined further because various articles suggest different cutoffs for what defines abnormal.^{33,47–51,70,90,91} The clinician's decision to treat a PDA was based on a comprehensive evaluation of these parameters.

Table 1.

Findings Suggestive of Hemodynamically Significant Patent Ductus Arteriosus (PDA)

Category	Characteristic
Clinical	Heart murmur Persistent tachycardia Active precordium Bounding pulses Low mean or diastolic blood pressure Widened pulse pressure High or increased ventilator settings or oxygen requirements/inability to extubate or wean from respiratory support High or increased number of apnea, bradycardia, or desaturation events Evidence of end organ dysfunction (e.g., low urine output, elevated creatinine, metabolic acidosis) Pulmonary hemorrhage Feeding intolerance
Radiographic	Cardiomegaly Pulmonary congestion/edema
Echocardiographic	Moderate to large transductal diameter Low (unrestrictive) pulsatile transductal flow Left-to-right shunt across the PDA Moderate to severe left heart pressure loading (e.g., elevated E:A ratio) Moderate to severe left heart volume loading (e.g., elevated LA:Ao ratio) Decreased, absent, or reversal of diastolic flow in the descending aorta, superior mesenteric artery, or renal artery
Biomarker	Elevated amino-terminal B-type natriuretic peptide

E:A ratio, early passive to late atrial contractile phase of transmural filling ratio; LA/Ao ratio, left atrium to aortic ratio; PDA, patent ductus arteriosus

At our institution, a course of medication management for hsPDA was defined as oral or IV IBU dosed 10 mg/kg on day 1, followed by 5 mg/kg every 24 hours for 2 doses, or oral or IV APAP dosed 15 mg/kg every 6 hours for 12 doses. Ibuprofen was generally selected as the drug of choice for initial pharmacologic treatment of hsPDA if there were no contraindications to its use (e.g., active intracranial hemorrhage or gastrointestinal bleeding, thrombocytopenia, coagulation defects, or significant renal dysfunction). Acetaminophen was prescribed for patients failing at least 1 course of IBU (defined as a persistent hsPDA after IBU) or in cases where IBU was contraindicated, provided there were no contraindications to APAP (e.g., acute or chronic liver disease). Ultimately, the selection of the pharmacologic agent was left to the discretion of the prescribing clinician.

Oral IBU and oral APAP use criteria for hsPDA treatment were developed and incorporated into the order set in the electronic health record. To promote preferential use of oral agents, the oral IBU and oral APAP treatment options were listed prior to their more costly IV counterparts in the order set, with the verbiage “unless contraindicated” added to the selection description. The criteria for oral therapy included patients tolerating at least gut prime feedings. Contraindications to oral treatment included patients with proven or suspected necrotizing enterocolitis, malabsorptive gastrointestinal condition, or any other contraindication to oral treatment as determined by the treating clinician. An initial 24-month medication use report was conducted to identify neonates prescribed IBU or APAP for the treatment of hsPDA. Data for this 24-month pre-criteria implementation period were collected from the electronic health record of patients seen between January 29, 2014, and January 28, 2016 (Era-1). In January 2016, criteria were introduced to preferentially prescribe oral therapy for hsPDA management. This was endorsed by our institution's Neonatal Critical Care Committee (a multidisciplinary committee led by neonatologists). Post-criteria implementation data were collected for a second 24-month period between January 29, 2016, and January 28, 2018 (Era-2).

Patient gestational age, birth weight, and sex were collected for each evaluation period. The number of patients, treatment courses, and total number of doses administered were quantified and stratified according to the medication selected, route of administration, and evaluation period. The number of patients requiring PDA ligations after pharmacologic treatment was collected for Era-1 and Era-2, and the groups were compared.

The drug costs used in this evaluation are summarized in Table 2 and reflect institutional contracted acquisition costs for each year of the study period. The cost per dose of the oral formulations equaled the acquisition cost of their respective unit-dose products. Intravenous IBU is FDA approved as a single-use vial. Per US Pharmacopeia <797>, single-dose vials of sterile products may only be used for up to 6 hours after initial needle puncture in an ISO class 5 or cleaner environment,⁹² and CDC guidance recommends against the use of single-dose vials for multiple patients.⁹³ Therefore, 1 vial of drug is used for a single administered dose, and each IV IBU dose incurs the full cost of the IV vial. Intravenous APAP is also marketed as a single-use product; however, data supporting 24-hour stability in IV syringes after accessing the vial are available for this formulation.^94,95 Transferring doses from the original vial to a syringe is considered a low-risk preparation and assigned a beyond-use date not to exceed 48 hours at room temperature in the absence of sterility testing.⁹² Based on stability data, CDC guidance, and US Pharmacopeia standards, 1 vial of IV APAP is used to dispense a 24-hour supply of the drug to a single patient.

Table 2.

Contracted Drug Acquisition Cost Per Vial (IV) or Unit Dose Container (Oral) by Study Year *

	Era-1†		Era-2‡
	Year 1	Year 2	Year 3	Year 4
Ibuprofen
Intravenous	507.50	507.50	507.50	555.71
Oral	0.57	0.54	0.53	0.53
Acetaminophen
Intravenous	14.12	33.28	33.11	35.11
Oral	0.56	0.56	1.08	1.08

* US dollars.

^† Era-1: Data were collected before preferred oral prescribing.

^‡ Era-2: Data were collected after preferred oral prescribing.

To calculate medication cost, the total number of administered IBU and APAP doses for Era-1 and Era-2 were tabulated and stratified by route of administration. The total number of administered oral APAP, oral IBU, and IV IBU doses per strata was multiplied by the medication's cost per single-dose vial or unit-dose product for the study year. For IV APAP, the cost of 1 vial corresponded to 24 hours of treatment. The costs for therapy in Era-1 and Era-2 were calculated by adding the total cost for each medication and their respective administration routes.

Descriptive statistics were used to characterize the data. A 2-sample t test for equal variance was used to compare continuous data. For nominal data, the χ² or Fisher exact test was used, the latter for data sets including cells with 5 or fewer observations. Statistical significance was defined as a p value less than 0.05.

Results

Baseline patient demographic data were comparable between the 2 groups (Table 3). The Era-1 group received 190 courses of treatment in 110 patients (1.73 ± 0.85 courses per patient), and the Era-2 group received 210 courses of treatment in 109 patients (1.92 ± 0.94 courses per patient). This difference was not statistically significant (p = 0.1). Table 4 lists the number of treatment courses per patient, and Table 5 indicates the number of administered doses per treatment course, both stratified by medication prescribed and route of administration; there were no statistically significant differences between the 2 eras.

Table 3.

Patient Demographics

Parameter	Era-1 (n = 110)*	Era-2 (n = 109)†	p value
Gestational age, mean ± SD, wk	25.9 ± 2.2	26 ± 2.3	0.81
Weight, mean ± SD, kg	0.81 ± 0.25	0.84 ± 0.33	0.5
Sex, male, n (%)	62 (56.4)	54 (49.5)	0.31

* Era-1: Data were collected before preferred oral prescribing.

^† Era-2: Data were collected after preferred oral prescribing.

Table 4.

Treatment Courses per Patient

Medication	Era-1 (n = 190)*	Era-2 (n = 210)†	p value
Ibuprofen, mean ± SD
Intravenous	1.27 ± 0.59	1.13 ± 0.48	0.27
Oral	1.2 ± 0.5	1.36 ± 0.61	0.18
Acetaminophen, mean ± SD
Intravenous	0.99 ± 0.39	1.29 ± 0.55	0.11
Oral	0.97 ± 0.42	1.21 ± 0.56	0.12

* Era-1: Data were collected before preferred oral prescribing.

^† Era-2: Data were collected after preferred oral prescribing.

Table 5.

Medication Doses per Treatment Course

Medication	Era-1*	Era-2†	p value
Ibuprofen, mean ± SD
Intravenous	3.8 ± 1.8	3.4 ± 1.4	0.27
Oral	3.6 ± 1.5	4.1 ± 1.8	0.18
Acetaminophen, mean ± SD
Intravenous	11.9 ± 4.7	15.5 ± 6.6	0.11
Oral	11.7 ± 5.1	14.5 ± 6.7	0.12

* Era-1: Data were collected before preferred oral prescribing.

^† Era-2: Data were collected after preferred oral prescribing.

There was a significant decrease in the total number of IV IBU doses administered in Era-2 compared with Era-1, accompanied by significant increases in oral IBU, IV APAP, and oral APAP administrations (Table 6). A total of 5 patients in Era-1 and 32 patients in Era-2 received APAP only as their pharmacologic treatment for hsPDA (i.e., no IBU administered as initial or second-line treatment), accounting for 55 doses (37 IV and 18 oral) and 591 doses (237 IV and 354 oral) in Era-1 and Era-2, respectively (p < 0.001).

Table 6.

Total Number of Doses per Medication

Medication	Era-1*	Era-2†	p value
Ibuprofen, n
Intravenous	335	81	<0.001
Oral	155	236	0.01
Acetaminophen, n
Intravenous	131	434	<0.001
Oral	187	813	<0.001

* Era-1: Data were collected before preferred oral prescribing.

^† Era-2: Data were collected after preferred oral prescribing.

Table 7 summarizes the costs incurred for pharmacologic treatment of hsPDA. Total IBU and APAP drug acquisition costs of $171,260.60 and $47,461.49 were calculated for Era-1 and Era-2, respectively, yielding a total cost savings of $123,799.21, or $61,899.61 per annum, in Era-2. The reduction in IV IBU use in Era-2 accounted for all the savings ($63,563.83 annually); however, increased use of oral IBU, IV APAP, and oral APAP during this era slightly reduced the annual net savings to $61,899.61. Annual savings increase to $70,808.47 if the data are adjusted for the 20 additional treatment courses administered in Era-2.

Table 7.

Cost Comparison ^*

Medication	Era-1†	Era-2‡	Net savings
Ibuprofen, n
Intravenous	170,012.50	42,794.85	127,215.65
Oral	85.35	125.08	−39.73
Acetaminophen, n
Intravenous	1,089.92	3,663.52	−2,573.60
Oral	72.93	878.04	−805.11
Totals
24-mo totals	171,260.70	47,461.49	123,799.21
Annual totals	85,630.35	23,730.75	61,899.61

* US dollars

^† Era-1: Data were collected before preferred oral prescribing

^‡ Era-2: Data were collected after preferred oral prescribing

Surgical corrections after medical treatment were performed in 41.7%, 33.9%, 30.8%, and 13.6% of patients in years 1 through 4 of the study, respectively. A total of 41 of the 110 patients (37.3%) in Era-1 and 26 of 109 patients (23.9%) in Era-2 required PDA ligations after pharmacologic treatment (p = 0.03).

Discussion

Various options exist for the management of neonatal PDA. When selecting a pharmacologic treatment option, the prescriber should consider the medication's efficacy, adverse effect profile, and cost. The authors calculated total drug costs by multiplying the total number of oral unit-dose products and IV vials used by their respective costs, and then adding all of the values per evaluation period. This method directly reflects the impact of the prescribing practice change on drug purchases, and consequently on the pharmacy department's budget, yielding an annual net savings of $61,899.61 in Era-2. However, financial impact may have also been approached from a cost-avoidance perspective whereby each administered dose of an oral medication would have been treated as a substitute for its more costly IV formulation. There were 155 and 236 oral IBU and 187 and 813 oral APAP doses administered in Era-1 and Era-2, respectively. If the cost differences between IV and oral IBU and IV and oral APAP per study year and era were used to calculate cost avoidance, savings would have calculated to $209,450.01 during the 4-year study, or $40.014.14 per annum in Era-1 and $64,711,32 per annum in Era-2. Using either method, the cost savings were comparable and accounted for in their entirety by reduction in use of IV IBU. Use of oral IBU, oral APAP, and IV APAP increased during this era, which slightly reduced the net annual savings.

The increased use of oral IBU, oral APAP, and IV APAP in Era-2 did not lead to a statistically significant increase in the mean number of patients receiving additional treatment courses to manage the hsPDA. This finding is consistent with literature that concludes that oral IBU and oral APAP are non-inferior to their IV formulation equivalents and to each other. Several meta-analyses have been published comparing PDA closure rates between APAP and IBU and comparing oral and IV routes of administration. Mitra et al⁵⁴ calculated higher overall PDA closure rates with standard doses of oral IBU and oral APAP compared with IV IBU (OR, 2.22; 95% CI, 1.44–3.40; and OR, 2.93; 95% CI, 1.53–5.62, respectively).⁵⁴ A Cochrane systematic review reported similar findings, with rates of failure to close the PDA lower for oral IBU compared with IV IBU (RR, 0.38; 95% CI, 0.26–0.56).⁸⁹ Another Cochrane review⁸² and 3 other meta-analyses^80,81,85 found no differences in rates of PDA closure between APAP and IBU, but APAP produced fewer adverse effects (gastrointestinal bleeding,^81,82,85 renal failure,^81,82 and hyperbilirubinemia^82,85). Recent data^54,84,87 also support oral APAP as non-inferior to oral IBU for closure of hsPDA in premature neonates.

Although the intention of this study was not to evaluate efficacy, there was a statistically significant reduction in PDA ligations in Era-2 compared with Era-1. A variety of confounding factors contribute to reductions in PDA ligation rates, including the general practice change in the neonatal community and at our institution to reduce surgical corrections for PDAs in Era-2.^{27,28,31,42,45} Therefore, the decrease in PDA ligations in Era-2 cannot be directly attributed to the observed changes in medication prescribing patterns, but the finding supports published literature reporting non-inferiority between the oral and IV routes of administration for IBU and APAP.^{54,58,59,63,71–78,88,89}

There were several limitations to this study. First, Era-1 and Era-2 had different numbers of treatment courses. Despite the greater number of treatment courses in Era-2, the total acquisition cost decreased compared with Era-1. If Era-1 costs are averaged on a per course basis and extrapolated to the number of courses in Era-2, the annual savings would have calculated even higher. Contracted drug costs varied throughout the 4-year study period, but the impact of these variations was accounted for by multiplying the number of doses administered by the cost of the drug for that year. Calculated savings may also have been affected by infrequent purchases made outside of contracted costs due to product availability limitations. Additionally, although cost savings may vary depending on changing drug costs over time, APAP and IBU costs at our institution were similar from time of study to time of analysis. Other limitations of this study include those inherent to retrospective reviews. Practice changes in the management of hsPDA occurred between the 2 eras that were not controlled for in this study. The increased use of APAP in Era-2 coincided with an increase in the number of publications supporting its efficacy and role in PDA management during that time,^{57–60,71,72} particularly as second-line therapy after IBU treatment failure or when IBU was contraindicated.^63–68 As neonatologists gained experience with prescribing APAP at our institution (including IV APAP in patients not tolerating enteral feedings), its use as first-line treatment also increased, principally in neonates with, or at risk for, adverse GI or renal effects associated with cyclooxygenase inhibitors. Another potential constraint was the exclusive use of the standard IBU dose regimen at our institution for both oral and IV routes of administration. High-dose IBU regimens (15–20 mg/kg on day 1, followed by 7.5–10 mg/kg every 24 hours for 2 doses) have been associated with increased hsPDA closure rates compared with standard dosing without an increase in adverse effects^54,89,96; therefore, adopting high-dose IBU regimens may lead to fewer repeat courses of pharmacotherapy, potentially decreasing costs further.

Conclusion

Prescribing IV IBU for the treatment of hsPDA remains a common practice in many US hospitals; however, the use of oral IBU and oral or IV APAP is expanding as literature supporting their use continues to increase. Prescribing lower-cost enteral formulations for the pharmacologic management of hsPDA led to medication cost savings in excess of $60,000.00 per year at our institution. Our findings should serve as a platform to scrutinize all costs incurred in the treatment of hsPDA and to promote implementation of changes necessary to reduce medication expenditures in NICU patients when supported by the evidence.

ABBREVIATIONS

APAP

acetaminophen

CDC

US Centers for Disease Control and Prevention

hsPDA

hemodynamically significant patent ductus arteriosus

IBU

ibuprofen

IV

intravenous

NICU

neonatal intensive care unit

PDA

patent ductus arteriosus