Patent Ductus Arteriosus: Philosophy or Pathology?

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1 Patent Ductus Arteriosus: Philosophy or Pathology? Disclosure Ray Sato, MD is a speaker for Prolacta Biosciences, Inc. This presentation will discuss off-label uses of acetaminophen and ibuprofen. RAY SATO, M.D TACOMA GENERAL HOSPITAL AND MEDNAX MEDICAL GROUP What is Quality Improvement with regard to PDA Management? In health care, quality improvement (QI) is the framework we use to systemically improve the ways care is delivered to patients. Processes have characteristics that can be measured, analyzed, improved and controlled. QI entails continuous efforts to achieve stable and predictable process results, that is, to reduce process variation and improve the outcomes of these processes Agency for Healthcare Research and Quality Quality Improvement Metrics for PDA Management PDA Prevalence PDA Treatment PDA Treatment Cost and Resource Utilization PDA Ligations PDA Management Process Variation PDA Prevalence at Discharge PDA Intervention after Discharge PDA Associated Morbidity Background Tacoma General NICU Population ( ) Average 141 VLBW Infants (<=1500 grams) yearly 62 ELBW infants (<=100 grams) yearly Treatment of Persistent PDA in Preterm Infants: Time to Accept the Null Hypothesis? Review of the medical literature about PDA management including 49 trials documenting substantial reduction in PDA patency with treatment. Pooled data clearly favored ductal closure in treatment & prophylaxis groups. No other statistically significant outcome difference was demonstrated including mortality, BPD, NEC, Sepsis, IVH, PVL, ROP, or late neurodevelopmental outcomes. Treatments that close the persistent PDA in preterm infants do not improve long term outcomes. Benitz, J Perinatology

2 Patent Ductus Arteriosus in Preterm Infants Early, routine treatment to induce closure of the ductus in preterm infants, either medically or surgically, in the first 2 weeks after birth does not improve long-term outcomes The role of more selective use of medical methods for induction of ductal closure, either for defined high-risk infants in the first 2 postnatal weeks, or more generally, for older infants in whom the ductus remains patent, remains uncertain and requires further study. Basis of PDA Management Decisions Committee on Fetus and Newborn, American Academy of Pediatrics, PDAs are Universal Mechanism of PDA Closure All Infants are born with PDAs, preterm infants are at higher risk for persistent patency. Term Infants: 1. More muscular tissue to close PDA and strangulate vasa vasorum Preterm infants: 1. Less muscular tissue making closure incomplete and vasa vasorum do not collapse 2. Thinner wall means oxygen can diffuse directly from PDA lumen preventing the fibrosis process 2. Many Premature Infants with PDA will Spontaneously Close Observational study of 65 VLBW Infants with serial echocardiograms until ligation, discharge or death. PDA treatment was reserved for infants with heart failure, acute renal impairment, or escalating respiratory therapy Spontaneous Closure ELBW Infants Spontaneous closure in ELBW infants demonstrated with q 48 hour echos on 122 enrolled infants in an observational study Spontaneous closure on Day 7: 67% for >1000 gram, 31% for <=1000 gram. 97% percent of the >1000 gram infants did not require intervention with spontaneous closure prior to discharge in 94% Nemerofsky, American Journal of Perinatology, 2008 Koch et al, Pediatrics

3 Spontaneous PDA Closure After Discharge Subsequent studies continued to support spontaneous closure in many patients even after discharge Spontaneous closure in 100% of 32 VLBW infants who were not treated 66% before discharge 34% after discharge 3. PDA Treatment & Prophylaxis Reduces Ductal Patency During Study Periods Herrman K, Arch Dis Child Fetal Neonatal Ed 2009 Benitz, J Perinatology, Optimal PDA Treatment Remains Elusive 300 infants <28 weeks Mean BW kg Treatment DOL 3 Medication Route: IV Acetaminophen El-Mashad, European Journal of Pediatrics 2017 Acetaminophen Meta-Analysis Cochrane Neonatal Review of 8 studies involving 916 patients Moderate-quality evidence suggests acetaminophen is as effective as ibuprofen, low-quality evidence suggests it as effective as indomethacin Some studies reported decreased complications with acetaminophen therapy including gastrointestinal bleeding, lower creatinine, and higher platelet counts and urine output. Neurodevelopment Outcomes after PDA Therapy with Acetaminophen Neurodevelopmental outcomes at months were assessed in a trial comparing oral acetaminophen (30 patients) with oral ibuprofen (31 patients) and Bayley Scales of Infant Development scores did not differ in the two groups Oncel, American Journal of Perinatology, Ohlsson, Cochrane Collaboration,

4 5. PDA Ligation is Associated with Adverse Outcomes Meta-analysis including 39 cohort studies and 1 randomized controlled trial comparing medical treatment with surgical therapy. Surgical PDA ligation was associated with Increases in neurodevelopmental impairment Chronic Lung Disease Severe Retinopathy of Prematurity Reduction in mortality was noted. Weisz, Pediatrics, 2014 Reducing Ligations Without Increasing Morbidity Observational study at UCSF following <=27 weeks infants with persistent PDA after indomethacin prophylaxis and indomethacin treatment (Failure rate 24% in both periods) Period infants underwent ligation Period infants managed conservatively with ligation only for cardiopulmonary compromise ultimately 72% of patients. Rates of BPD, Sepsis, ROP, ROP, Neurologic injury and death were similar Rate of NEC was significantly lower in period 2 Jhaveri, Journal of Pediatrics PDA Treatment Timing Evidence is Insufficient Almost all enrolled patients in PDA trials were treated within first 2 weeks after birth. Available evidence is insufficient to permit assessment of potential benefits of treatments initiated after 2 weeks of age. Benitz, J Perinatology Indomethacin Prophylaxis Benefits Questioned The TIPP trial of Low-dose indomethacin reported a decrease in severe IVH grade 3 /4 from 13% to 9% (p 0.02) in a randomized trial of 1202 infants grams. 18 Month follow up data found no improvement in survival without neurosensory impairment despite decreased severe IVH and PDA Patent ductus Arteriosus Data Echo confirmed PDA Indomethacin Placebo p Value 24% 50% <0.001 Medical Tx PDA 17% 46% <0.001 PDA Ligation 7% 12% Schmidt, NEJM, 2001 Indomethacin Prophylaxis and PDA Ligations Canadian retrospective cohort study of 4268 infants <1000 grams at birth Prophylactic indomethacin was associated with increased odds of spontaneous intestinal perforation 5.2% vs 2.7% Stavel, Journal of Perinatology 2017 Prophylactic Indomethacin Does Not Influence BPD Rate Retrospective analysis of 7831 ELBW infants cared for at NICHD centers between infants received prophylactic indomethacin 5244 infants did not Prophylactic indomethacin was not associated with either reduced or increased risk of BPD or Death 54.3% in prophylaxis group 51.1% in no prophylaxis group Jensen, Journal of Pediatrics

5 8. Need for PDA Treatment Remains Unsettled South Korean retrospective review of 178 infants weeks gestation with PDA. In Period 1 ( ) n=81, 64% of infants were treated with indomethacin, and ultimately 82% required surgical ligation. In Period 2 ( ) n=97 PDAs were managed conservatively with fluid restriction, diuretics and respiratory support. 5 infants (5%) had PDAs open until discharge. 3 of the 5 infants ultimately required transcatheter occlusion at 10, 12 and 13 months of age. A nonintervention approach of judicious fluid restriction and prn use of diuretics without indomethacin and/or ligation was not associated with increased mortality or morbidities such as NEC or IVH. Nonintervention was associated with significantly less BPD than mandatory closure (58% vs 38%) Sung, Journal of Pediatrics 2016 Conservative PDA Treatment Without Morbidity Retrospective US study comparing Era with active PDA management and second era without medical of surgical treatment Treat (n=415) No Treat (n=228) p-value Mohamed, J Perinatology, 2017 Mohamed Study In the treatment era, 23.1% of infants received medical therapy and 3.6% required PDA ligation Mohamed Study Secondary Outcomes Tacoma QI PDA Initiatives Cycle Infants <26 weeks continued to be treated medically if no contraindications existed, but infants weeks were observed until at least a week old and infants >28 weeks for two weeks before embarking on medical therapy unless significantly compromised Ligations were continued if medical therapy failed and patient significantly impacted. Cycle PDAs observed only unless significant clinical impact for all gestations. Medical therapy for: Hypotension requiring therapy Pulmonary edema resulting in significant pulmonary deterioration (intubation, substantial increase in support) Pulmonary Hemorrhage Metabolic acidosis Surgical ligation only for recalcitrant cases Tacoma PDA Ligation Rate Decreased ELBW Infants 5

6 Tacoma Morbidity/Mortality ELBW University of Miami Ibuprofen Trial Masked Randomized trial 105 infants ( grams) comparing early ibuprofen therapy with expectant management focusing therapy only on infants with hemodynamically significant PDA (pulmonary hemorrhage, hypotension requiring 10 mcg/kg-min of dopamine, respiratory deterioration attributed to PDA) Enrolled infants who developed mild symptoms of PDA and confirmed with echocardiogram, patients received masked ibuprofen or placebo. Infants who met hemodynamically significant definition at enrollment were excluded. After completion of the initial course of study drug, infants who developed symptoms of hemodynamically significant PDA confirmed with echocardiogram, Open label ibuprofen was given. 13% of early treatment patients required open label Ibuprofen 20% of expectant management patients required open label Ibuprofen Miami Ibuprofen Trial Findings Study was terminated before planned enrollment reached due to removal of Neoprofen from the US Market Early treatment infants received Ibuprofen at day 3 to 4, expectant management patients received open label ibuprofen at a mean of 11 days. 49% of expectant management group did not require any PDA treatment. Ultimately 14% of early treatment patients and 20% of expectant management patients required surgical ligation. No difference if mortality, intestinal perforation, surgical NEC, advanced IVH, PVL, sepsis or ROP Increased Lung disease (FiO2 >30% at 36 weeks corrected) in infants with early ibuprofen therapy did reach statistical significance 17% in early treatment group vs 4% in expectant management. Pediatrix Data Clinical Data Warehouse Reports Decreased PDA Intervention Review of records of 61,520 infants in 280 US NICUs weeks gestation Bixler, J Pediatrics, Prophylaxis? Making a PDA Treatment Strategy Ibuprofen prophylaxis has not been shown to reduce IVH. Indomethacin prophylaxis reduces advanced IVH but not rate of survival without neurosensory impairment at 18 months and adverse neurodevelopmental function at 54 months. Indomethacin prophylaxis reduces PDA, PDA treatment and surgical ligation but variation in TIPP center PDA management makes it difficult to draw conclusions. Schmidt, The New England Journal of Medicine,

7 Prophylaxis Decisions Treatment Decisions Reduction of advanced IVH would be primary consideration Therapy for PDA exposes large numbers of patients to unnecessary treatment that has not been proven to benefit long term If benefits of treatment are questionable, select the equally effective medication with the least side effects with the additional advantages of minimal contraindications and cheaper cost. Widespread experience on all age groups Minimal contraindications Bleeding effects are minimal (advanced IVH) No evidence of NEC association Acetaminophen can be given oral or IV Feedings may continue with acetaminophen therapy Benitz, Journal of Perinatology 2010 Acetaminophen Cost (2018) Manage PDAs like VSDs? IV Ibuprofen (Neoprofen) 20 mg per vial (treatment course 20 mg/kg with average weight 779 mg) requires 15.6 mg. Each vial costs $250. IV Acetaminophen (Ofirmev) 1000 mg per vial, cost $37. Oral acetaminophen negligible cost In addition to drug costs, supportive care for NPO patients including IV access and IVF/TPN are required. Everyone is born with a PDA but only some have VSDs Both PDAs and VSDs may lead to pulmonary over circulation and congestive heart failure especially for preterm infants Premature infants with VSDs cannot undergo closure PA Band applied if medical management (fluid restriction, diuretics, digoxin) fails whereas PDAs can be closed medically or surgically Medical closure less successful with increasing age PDA size relatively less significant with infant growth PDA Treatment at Tacoma General 2014 TG Demographics Jan 2016-June 2018 PDAs observed only unless significant clinical impact for all gestations. Medical therapy for: Hypotension requiring therapy Pulmonary edema resulting in significant pulmonary deterioration (intubation, substantial increase in support) Pulmonary Hemorrhage Metabolic acidosis As of 2014, Acetaminophen used as first line therapy Surgical ligation only for recalcitrant cases Echos at 2 weeks if PDA suspected regardless of clinical impact to r/o alternate congenital heart diseases <1000 Grams <25 weeks Gestation Patients Survival 128 (82%) 49 (76%) PDA Treatment 53 (34%) 25 (39%) PDA Ligations in NICU 6 (3.9%) 2 (5.8%) PDA Closure Post NICU 3 3 7

8 Results of PDA Treatment ELBW Morbidity and Mortality <1000 Grams <25 Weeks Acetaminophen Treatment Started (DOL) Duct Smaller 29 (56%) 14 (56%) Duct Closed 7 (14%) 3 (12%) Ibuprofen 7 4 PDA Open at Discharge 18 (3 ligated post NICU) 11 (3 ligated post NICU) Deaths in PDA Group 3 1 Conclusions PDA management is an important contributor to good clinical outcomes for premature infants Quality Improvement entails continuous efforts to achieve stable and predictable process results, that is, to reduce process variation and improve the outcomes of these processes In absence of generally accepted optimal care guidelines, each NICU needs to evaluate the literature despite the wide variation in clinical management Bibliography Benitz W, Treatment of Persistent Patent Ductus Arteriosus in Preterm infants: Time to Accept the Null Hypothesis? Journal of Perinatology 2010; 30; Benitz W for the Committee on Fetus and Newborn, Patent Ductus Arteriosus in Preterm Infants, Pediatrics 2016; 137:1. Bixler G, Changes in the Diagnosis and Management of PDA from 2006 to 2015 in US NICUs, Journal of Pediatrics 2017; 189; El-Mashad A, Comparative Study of the Efficacy and Safety of Paracetamol, Ibuprofen, and Indomethacin in Closure of PDA in Preterm Neonates, European Journal of Pediatrics 2017; 176; Herrman K, Spontaneous Closure of the Patent Ductus Arteriosus in VLBW Infants Following Discharge from the Neonatal Unit, Archives Diseases Childhood Fetal Neonatal Edition 2009; 94; F48-F50 Jensen E, Association Between Use of Prophylactic Indomethacin and the Risk for Bronchopulmonary Dysplasia in Extremely Preterm Infants, Journal of Pediatrics 2017; 186; Jhaveri N, Early Surgical Ligation Versus a Conservative Approach for Management of PDA that Fails to Close after Indomethacin Treatment, Journal of Pediatrics 2010; 157; Koch J, Prevalence of Spontaneous Closure of the Ductus Arteriosus in Neonates at a Birth Weight of 1000 grams or less, Pediatrics 2006; 117 (4); Nemerofsky, The Ductus Arteriosus Rarely Requires Treatment in Infants >1000 Grams, American Journal of Perinatology 2008; 25 (10); Ohlsson A, Paracetamol for PDA in Preterm or Low Birth Weight Infants, Cochrane Database of Systemic Reviews 2018, Issue 4. Oncel M, Neurodevelopmental Outcomes of Preterm Infants Treated with Oral Paracetamol Versus Ibuprofen for PDA, American Journal of Perinatology 2017; 34(12); Schmidt B, Long-Term Effects of Indomethacin Prophylaxis in ELBW Infants, The New England Journal of Medicine 2001; 344 (26); Sosenko I, Timing of PDA Treatment and Respiratory Outcome in Premature Infants: A Double Blind Randomized Controlled Trial, Journal of Pediatrics 2012; 160; Stavel M, Effect of Prophylactic Indomethacin Administration and Early Feeding on Spontaneous Intestinal Perforation in ELBW, Journal of Perinatology 2017; 37; Sung S, Mandatory Closure Versus Nonintervention for PDA in Very Preterm Infants, Journal of Pediatrics 2016; 177; Weisz D, PDA Ligation and Health Outcomes: A Meta-analysis, Pediatrics 2014; 133; e1024-e