Prospective Economic Evaluation Alongside the Nasal Intermittent Ventilation Trial

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Prospective Economic Evaluation Alongside the Nasal Intermittent Ventilation Trial
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Mowitz, Meredith Elizabeth
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Master's ( M.S.)
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University of Florida
Degree Disciplines:
Medical Sciences, Clinical Investigation (IDP)
Committee Chair:
BRANTLY,MARK LOUIS
Committee Co-Chair:
BURCHFIELD,DAVID JAMES

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cost-effectiveness -- neonate
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Abstract:
Non-invasive ventilation strategies are commonly used as a means of avoiding intubation and its consequences in premature infants. Recently, a large randomized controlled trial compared the use of nasal continuous positive airway pressure (nCPAP) to nasal intermittent positive pressure ventilation (NIPPV) as a method to reduce bronchopulmonary dysplasia (BPD).1 While no significant difference in the primary outcome was found, the economic implication of using one strategy over the other needed evaluation. We sought to determine the cost effectiveness of nCPAP compared to NIPPV for improvement in survival without BPD in infants with birth-weights less than 1,000 grams. Using patient level data from the clinical trial, we undertook an economic evaluation. We measured costs from a third party payer perspective, with a time horizon through discharge, death or 44 weeks post-menstrual age. After directly comparing costs between treatment arms, we performed a formal economic evaluation using the primary outcome of the trial, survival without BPD. The mean cost of hospitalization per infant was higher in the NIPPV group, $205,309, compared to the nCPAP group, $196,836. Similarly, there was a 69% probability that NIPPV is both more expensive and less effective than nCPAP and only a 2.4% probability that it is less costly and more effective. Although clinically equal in the trial, formal economic evaluation reveals that using NIPPV is an economically unfavorable strategy. This confirms that the resource implications of clinical therapies may be independent of the primary biological outcome of a trial, and should be routinely included in assessments of therapies.
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by Meredith Elizabeth Mowitz.
Thesis:
Thesis (M.S.)--University of Florida, 2014.
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Adviser: BRANTLY,MARK LOUIS.
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Co-adviser: BURCHFIELD,DAVID JAMES.

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PROSPECTIVE ECONOMIC EVALUATION ALONGSIDE THE NASAL INTERMITTENT VENTILATION TRIAL By MEREDITH E. MOWITZ A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2014

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2014 Meredith E. Mowitz

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To m y h usband, c hildren and p arents

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4 ACKNOWLEDGMENTS I would like to thank my mentors, Dr. John Zupancic and Dr. Dmitry Dukovny who have graciously given of their time and energy to guide me through the world of economic evaluations as well as Dr. David Burchfield for his support of my research. Dr. Haresh Kirpalani and the NIPPV study group for their excellent clinical trial wit hout which this evaluation would not be possible. I would also like to thank Ms. Eve Johnson for her guidance and editorial assistance. Personally, I would like to thank my husband, Justin Mowitz, for his encouragement and support that allows me to pur sue my interests and my children, Avery and Carson, for always providing a smile at the end of some very long days. Finally, to my parents who h ave always stood by my side fostering m y learning and supporting my dreams.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 6 LIST OF FIGURES ................................ ................................ ................................ .......... 7 LIST OF ABBREVIATIONS ................................ ................................ ............................. 8 ABSTRACT ................................ ................................ ................................ ..................... 9 CHAPTER 1 BACKGROUND ................................ ................................ ................................ ...... 11 Ventilation of Premature Infants ................................ ................................ .............. 11 Non Invasive Ventilation ................................ ................................ ......................... 11 2 METHOD S ................................ ................................ ................................ .............. 13 Overview of the NIPPV Trial ................................ ................................ ................... 13 Framing of the Economic Evaluation ................................ ................................ ...... 13 Resource Utilization, Costs and Effects ................................ ................................ .. 14 Statistical Considerations ................................ ................................ ........................ 14 3 RESULTS ................................ ................................ ................................ ............... 18 Outcome of NIPPV Trial ................................ ................................ .......................... 18 Resource Utilization ................................ ................................ ................................ 18 Direct Cost Comparison ................................ ................................ .......................... 19 Cost Effectiveness Analysis ................................ ................................ .................... 19 4 DIS CUSSION AND CONCLUSIONS ................................ ................................ ...... 22 Economics of Non Invasive Ventilation ................................ ................................ ... 22 Limitations ................................ ................................ ................................ ............... 22 Conclusion ................................ ................................ ................................ .............. 23 LIST OF REFERENCES ................................ ................................ ............................... 25 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 28

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6 LIST OF TABLES Table page 2 1 Costs for hospital and physician per diem ................................ .......................... 16 3 1 Resource utilization ................................ ................................ ............................ 20 3 2 Leng th of stay and respiratory support ................................ ............................... 20 3 3 Direct cost comparison ................................ ................................ ....................... 20

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7 LIST OF FIGURES Figure page 3 1 Incremental cost effectiveness ratio (iCER) plot ................................ ................. 21

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8 LIST OF ABBREVIATIONS BPD Bronchopulmonary dysplasia iCER Incremental cost effectiveness ratio nCPAP Nasal continuous positive airway pressure NEC Necrotizing enterocolitis NIPPV Non i nvasive positive pressure ventilation or nasal intermittent positive pressure ventilation PDA Patent ductus arteriosis PMA Post menstrual age pRBC Packed red blood cell ROP Retinopathy of prematurity

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9 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science PROSPECTIVE ECONOMIC EVALUATION ALONGSIDE THE NASAL INTERMITTENT VENTILATION TRIAL By Meredith E. Mowitz M ay 2014 Chair: Mark Brantley Major: Medical Sciences Clinical and Translational Science Non invasive ventilation strategies are commonly used as a means of avoiding intubation and its consequences in prema ture infants. Recently, a large randomized controlled trial compared the use of nasal continuous positive airway pressure (nCPAP) to n asal i ntermittent p ositive p ressure v entilation (NIPPV) as a method to reduce b ronchopulmonary dysplasia (BPD) 1 While no significant difference in the primary outcome was found the economic implication of using o ne strategy over the other needed evaluation We sought t o determ ine the cost effectiveness of nCPAP compared to NIPPV for improvement in survival wi thout BPD in infants with birth weights less than 1,000 grams Using patient level data from the c linical trial, we undertook an economic evaluation. We measured costs from a third party payer perspective, with a time horizon through discharge, death or 44 weeks post menstrual age After directly comparing costs between treatment arms, we performed a formal economic evaluation us ing the primary outcome of the trial, survival without BPD. The mean cost of hospitalization per infant was higher in the NIPPV group, $205,309, compared to the nCPAP group, $196,836. Similarly, there was a 69%

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10 probability that NIPPV is both more expensive and less effective than nCPAP and only a 2.4% probability that it is less costly and more effective Although clinically equal in the trial, formal economic evaluation reveals that using NIPPV is an economically unfavorable strategy. This confirms that the resource implications of clinical therapies may be independent of the primary biological outcome of a trial, and should be routinely included in assessments of therapies

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11 CHAPTER 1 BACKGROUND Ventilation of Premature Infants In the United States 11.5% of infants are born prematurely leading to an estimated societal cost of over $26 billion 2,3 Premature infants are classified as those delivered prior to 37 weeks gestation. Given their early entry, these infants are at risk of numerous complications and require in tensive care for an extended period of time. Respiratory difficulties are among the most common morbidities faced in this population and m any premature infants require respiratory support during their first days to weeks of life. For the smallest infants the mainstay of treatment is invasive ventilation such as intubation and mechanical ventilation 4 However, the use of invasive ventilation increases lung injury, and in some cases, causes bronchopulmonary dysplasia (BPD) or even death 5 Bronchopulmonary dysplasia, a chronic lung disease characterized by prem ature infants who remain oxygen dependent at 36 weeks corrected gestational age, occurs in approximately 22 % of premature infants 6 The degree of injury and risk of death are directly related to the duration and intensity of the invasive ventilation. Consequently, neonatologi sts are searching for a way to decrease the amount of time premature infants spend on invasive assisted ventilation in order to decrease lung injury and potentially BPD as well as improve survival. Non Invasive Ventilation N asal continuous positive pressur e (nCPAP) is one means to avoid invasive ventilation. nCPAP provides positive pressure by way of nasal mask or prongs to stent open the upper airway. Many studies have shown the use of nCPAP decreases the

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12 need for and risks associated with invasive vent ilation 7 9 Therefore, neonatologists use nCPAP as a first line therapy to avoid intubation or a s a bridge to discontinue use of invasive support. N asal intermittent positive pressure ventilation (N IPPV ) provides the same continuous positive pressure as nCPAP with the addition of an intermittent peak inspiratory pressure. As a result, neonatologists have proposed NIPPV as an alternative to nCPAP hoping it confers greater benefit than nCPAP. Studies completed thus far comparing nCPAP to NIPPV have mixed results 10 Kir palani, et al undertook a large international, multi center, randomized control trial testing the use of nCPAP vs. NIPPV to preven t BPD or death in infants with birth weights less than 1,000 grams 1 In the study, the composite outcome of BPD or death was n ot significantly different between the groups (38.4% vs. 36.7%; p = 0.56) 1 This study is the largest to date with over 1,000 infants enrolled and raises the question of which non invasive ventilation strategy to use if both are equally efficacious. Even though the two strategies of non invas ive ventilation (nCPAP and NIPPV ) may be equally efficacious their use may have differing costs. Therefore, cost may help neonatologists decide which treatment to use in premature infants. Consequently, we undertook an economic evaluation of the NIPPV trial to determine the cost effectiveness of the two therapies.

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13 CHAPT ER 2 METHODS Overview of the NIPPV Tr ial The NIPPV study group lead by Kirapalani undertook a trial comparing noninvasive ventilation strategies in preterm infants Infants less than 30 weeks gesta tion and less than 1,000g birth weight who required non i nvasive ventila tion were enrolled from 36 sites in 10 countries including the United States, Canada, the United Kingdom, Ireland, Netherlands, Sweden, Belgium, Austria, Singapore, and Qatar In total, 1009 patients were randomized to receive either nCPAP or NIPPV at the time they need ed non invasive respiratory support within the first 28 days of life The primary outcome was reported as a composite of death or broncho pulmonary dysplasia (BPD) as defined by a supplemental oxygen requirement at 36 weeks po st menstrual age (PMA) or a positive oxygen reduction test. Infants were followed until 44 weeks PMA, discharge or death whichever occurred first. The study had 80% power to determine a 20% relative risk reduction in the primary outcome. Framing of t he Economic Evaluation The prospectively planned economic evaluation was completed alongside the clinical trial using individual, patient level data. The third party payer perspective was used with time horizon through discharge, death or 44 weeks PMA. This was equivalent to the endpoint used in the NIPPV trial. Either United States costs or Canadian costs were applied according to the payer system that mostly closely matched that of the local medical system. Conversion to 2013 currency was completed using country specific health consumer price indices 12 14 Finally, country specific currency was converted to US dollars similar to previous evaluations 11,15,16

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14 Resource Utilization, Costs and Effects Resource utilization data was collected from the case report forms provided from the NIPPV trial. First, from these forms, the total number of hospi tal days and acuity was determined. Patients were assigned an acuity based on respiratory support. Next, using the acuity, a per diem rate for hospital services was assigned. Hospital per diem costs inc luded nursing and other support staff time, diagnostic procedures, nutrition (both enteral and parenteral), respiratory support, hospital overhead and equipment. Physician per diem costs covered physician time and services. These were calculated in a sim ilar manner as hospital per diem fees by classification of care day by acuity. Acuity for physician fees was based on respiratory support age and route of nutrition Per diem costs used in the analysis are seen in Table 2 1 Using the combination of co sts for physician per diem and hospital per diem a total cost for hospitalization was determined for each patient as well as an average for each arm of the study (NIPPV vs. nCPAP). The primary outcome from the clinical trial was used to calculate the incre mental cost effectiveness ratio. The inverse of the published outcome, survival without BPD at 36 weeks corrected gestational age was used as the measure of effectiveness for the evaluation. Statistical Considerations First, we completed a direct cost comparison by calculating the mean costs for each treatment arm as outlined above. Second, we calculated the incremental cost effectiveness ratio (iCER) as the difference in mean costs between the two study arms divided by the difference in mean effect b etween the two study arms. We assessed uncertainty using deterministic and probabilistic sensitivity analyses, including

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15 nonparametric bootstrapping. To accomplish this, simulated repetitions of the data set were obtained and mean costs, mean effects an d the iCER was calculated. A total of 1,000 simulated repetitions were performed 17 19

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16 Table 2 1 Costs for hospital and physician per d iem 20,21 Per diem Country Respiratory s upport Day of l ife Cost in 2013 US d ollars Hospital p er diem United States Mechanical v entilation A ll $2,499.78 nCPAP or NIPPV A ll $2,132.24 Nasal c annula A ll $962.91 Room a ir A ll $825.71 Canada Mechanical v entilation A ll $2,831.75 nCPAP or NIPPV A ll $2,831.75 Nasal c annula A ll $1,968.59 Room a ir A ll $1,968.59 Physician p er diem United States Mechanical v entilation 1 $934.27 nCPAP or NIPPV 1 $934.27 Nasal c annula 1 $342.27 Room a ir 1 $342.27 Mechanical v entilation 2 28 $384.80 nCPAP or NIPPV 2 28 $384.80 Nasal c annula and PMA less than or equal to 31 weeks 2 28 $137.45 Room a ir and PMA less than or equal to 31 weeks 2 28 $137.45 Nasal c annula and PMA 31 1/7 35 weeks 2 28 $124.86 Room a ir and PMA 31 1/7 35 weeks 2 28 $124.86 Nasal c annula and PMA equal to or more than 35 1/7 weeks 2 28 $116.70 Room a ir and PMA equal to or more than 35 1/7 weeks 2 28 $116.70 Mechanical v entilation 29 and up $396.71 nCPAP or NIPPV 29 and up $396.71 Nasal c annula and PMA less than or equal to 31 weeks 29 and up $137.45 Room a ir and PMA less than or equal to 31 weeks 29 and up $137.45 Nasal c annula and PMA 31 1/7 35 weeks 29 and up $124.86 Room a ir and PMA 31 1/7 35 weeks 29 and up $124.86 Nasal c annula and PMA equal to or more than 35 1/7 weeks 29 and up $116.70 Room a ir and PMA equal to or more than 35 1/7 weeks 29 and up $116.70 Canada Mechanical v entilation 1 $440.34

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17 Table 2 1. Continued Per diem Country Respiratory s upport Day of l ife Cost in 2013 US d ollars Physician per diem (continued) Canada (continued) nCPAP or NIPPV 1 $440.34 Nasal c annula and on parental nutrition 1 $302.15 Nasal c annula and no parental nutrition 1 $190.90 Room a ir and on parental nutrition 1 $302.15 Room a ir and no parental nutrition 1 $190.90 Mechanical v entilation 2 30 $220.11 nCPAP or NIPPV 2 30 $220.11 Nasal c annula and on parental nutrition 2 or more $151.04 Nasal c annula and no parental nutrition 2 or more $95.45 Room a ir and on parental nutrition 2 or more $151.04 Room a ir and no parental nutrition 2 or more $95.45 Mechanical v entilation 31 and up $109.96 nCPAP or NIPPV 31 and up $109.96

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18 CHAPTER 3 RESULTS Outcome of NIPPV Trial In total, 1,009 patients were enrolled in the NIPPV trial, with 504 in the NIPPV gro up and 505 in the nCPAP group. Seven patients in the NIPPV group were excluded secondary to not receiving an oxygen reduction test and 15 patients in the nCPAP group (13 missing oxygen reduction test a nd 2 withdrew consent) were excluded leaving 987 for analysis With the exception of male sex (p=0.04), the baseline characteristics of the nCPAP group and NIPPV group were not different 1 No significant difference was observed for the primary outcome, death or BPD, between the two groups (38.4% vs. 36.7%; p=0.56 ). Additionally no significant differences were seen in the secondary outcomes including: air leaks, pulmonary hemorrhage, patent ductus arteriosis (PDA), PDA ligation, nosocomial sepsis, meningitis, culture confirmed meningitis, pneumonia, any retinopath y of prematurity (ROP), severe ROP, brain injury, nasal trauma, confirmed necrotizing enterocolitis (NEC), death before discharge, reintubation after randomization 1 Resource Utilization Resources used by each group from the time of randomization to the primary endpoint (death, discharge or 44 PMA) are summarized in Table 3 1. Resource utilization for medications and procedures b etween the two groups did not differ significantly. As seen in Table 3 2, t here was a trend towards a longer hospitali zation in the NIPPV group (91 days) when co mpared to the nCPAP group (88 days). When further broken down, the NIPPV group remained on no n invasive ventilation, defined as nasal CPAP or NIPPV, longer than the nCPAP group. On average, the NIPPV group

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19 used non invasi ve ventilation support for 32 days compared to of 29 days (p=0.04) (Table 3 2) Direct Cost Comparison Ta ble 3 3 shows the average costs for hospital per diem and physician per diem fees which did differ significantly. The NIPPV group had higher per diem hospital and per diem physician costs on average compared to the nCPAP group. When totaled, t he nCPAP in average cost per hospitalization was less, $196,837, than the NIPPV group, $205,309, although this did not reach statistical significance (p value = 0.11 ). Cost Effectiveness Analysis The incremental cost effectiveness ratio ( iCER ) plot (Figure 3 1) shows the cost eff ectiveness analysis The mean cost difference and mean effectiveness difference for each of the 1,000 bootstrap replications are shown. From this plot we see that 69% of the replications lie in the upper left quadrant, which represents the dominated situation of increased cost and decreased effect. Moreover, 3% of the plots lie in the lower right quadrant, dominant, which indicates that it is unlikely NIPPV is both less costly and more effective than the use of nCPAP (Figure 3 1).

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20 Table 3 1 Resource utilization Parameter NIPPV (n=497) nCPAP (n=490) p value Length of Stay 91.01 (33.06) 88.16 (31.06) 0.16 Antibiotics 20.31 (17.75) 19.74 (17.50) 0.62 Antifungals 16.48 (17.29) 14.88 (14.59) 0.34 Surfactant 1.14 (0.38) 1.13 (0.36) 0.80 Indomethacin 2.85 (1.50) 2.89 (1.70) 0.86 Ibuprofen 3.43 (1.61) 3.36 (1.99) 0.83 Caffeine 48.75 (22.38) 48.73 (22.61) 0.99 Loop diuertics 6.60 (8.99) 7.55 (0.66) 0.25 Thiazide diuretics 25.33 (23.44) 25.93 (22.45) 0.84 Corticosteroids 10.12 (13.17) 10.07 (12.47) 0.56 Inhaled steroids 20.34 (23.44) 17.91 (22.85) 0.62 Inhaled bronchodilators 18.09 (21.68) 19.56 (24.40) 0.64 Inhaled nitric oxide 7.48 (7.54) 9.65 (18.09) 0.61 Vitamin A 10.83 (6.26) 11.84 (6.89) 0.39 pRBC transfusion 4.50 (3.98) 4.49 (3.92) 0.97 Perenteral nutrition 26.48 (22.14) 25.39 (21.29) 0.43 Surgery for NEC 9.32 (20.60) 6.88 (16.13) 0.55 Chest X ray 9.54 (8.64) 6.62 (8.73) 0.91 Abdominal X ray 5.23 (5.29) 5.42 (5.73) 0.63 Echocardiogram 2.73 (2.13) 2.83 (2.36) 0.58 Table 3 2 Length of stay and respiratory support NIPPV mean days (std. dev) nCPAP mean days (std. dev) p value Length of stay 91 (33) 88 (31) 0.16 Mechanical ventilation 13 (18) 13 (18) 0.86 nCPAP or NIPPV 32 (19) 29 (19) 0.04 Nasal cannula 13 (15) 13 (15) 0.74 Room air 5 (11) 7 (12) 0.15 Table 3 3 Direct cost comparison NIPPV group mean (SD) nCPAP group mean (SD) p value Physician per diem $17,231 ($9,942) $16,588 ($9,582) 0.30 Hospital per diem $186,696 ($81,260) $179,456 ($77,007) 0.15 T otal c ost $205,309 ($84,681) $196,837 ($9,203) 0.11

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21 Figure 3 1. Incremental cost effectiveness ratio (iCER) plot

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22 CHAPTER 4 DIS CUSSION AND CONCLUSIONS Economics of Non Invasive Ventilation For this economic evaluation, we used patient level data from a multi center randomized controlled trial. This evaluation analyzed costs in relation to the type of non invasive ventilation received during hospitalization until the time of discharge, death or 44 weeks post menstrual age These costs were then evaluated in terms of outcome for the complete analysis. For infants assigned to the NIPPV group, overall costs were higher compared to the nCPAP group. When these costs were put in perspective with the outcomes of the NIPPV tria l, NIPPV appears to be dominated by nCPAP. In other words, NIPPV is more costly and slightly less effective when compared to nCPAP (i.e. economically unfavorable). Limitations D ue to limitations in gathering cost data, some patient data required imputati on of costs outside their country of origin. When this occurred we chose to impute costs from Canada We cho se Canada because the health care payer system most similarly represents that found in the other countries (United Kingdom, Ireland, Sweden, Nether lands, Belgium, Austria, Singapore and Qatar). H owever, u sing costs from all countries individually would have allow ed for better understanding of the relationship between resource utilization and cost of health care. The disadvantages of not using hom e country costs in this international setting include differences in outcome patterns, practice variation and comparing prices across the countries 17 Although this may reduce the ability to generalize these findings to the other countries in the trial this practic e of applying a single countr costs is widely accepted in economic

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23 evaluations 25 Future analysis of this data set will include home country costs were they are able to be obtained. Additionally subgroup analysis by country will be differentiate Second for this analysis we have chosen the third party payer perspective in which s ocietal costs are not accounted for Ideally the societal costs would be included as they could contribute significantly to the total cost of prematurity. Future studies being designed by this author will address this issue with re analysis of this data set Finally, additional resources such as operations, radiographic studies, procedures and medications were not included in the costs for this analysis. This approach was taken as most of the countries represented use a system of bundled services. In these cases no additional fees are charged fo r studies and medications. Although theoretically there is additional cost associated with these procedures it is difficult to determine what this cost may be in the setting of bundled billing. Additionally, given that resource utilization between the gr oups was not significantly different it is unlikely that this will significantly change the result. Again, future analysis of this data set will include costs for major procedures, surgeries, radiographic studies and medications to determine if this has a n impact in the overall result. Conclusion This prospectively planned economic evaluation calls into question the use of NIPPV as a non invasive strategy over traditional nCPAP. Although a newer technology and equally clinically efficacious to nCPAP, NI PPV is economically unfavorable in the patient population studied, i.e., those less than 30 weeks gestational age requiring non invasive support. This study further supports the idea that clinical

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24 outcomes are not always in line with resource and economic implications advocating for concurrent economic evaluations in all clinical trials.

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25 LIST OF REFERENCES 1. Kirpalani H, Millar D, Lemyre B, Yoder BA, Chiu A, Roberts RS. A trial comparing noninvasive ventila tion strategies in preterm infants. The New England journal of medicine 2013;369(7):611 20. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23944299. Accessed September 30, 2013. 2. Martin JA, Hamilton BE, Osterman MJ, Curtin S, Mathews T, Statistics D o f V. Births: Final Data for 2012. National Vital Statistics Reports 2013;62(9). 3. Behrman RE, Butler AS. Societal Costs of Preterm Birth .; 2007. 4. Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonata l Research Network. Pediatrics 2010;126(3):443 56. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2982806&tool=pmcentrez&re ndertype=abstract. Accessed December 8, 2013. 5. Fischer HS, Bhrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta analysis. Pediatrics 2013;132(5):e1351 60. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24144716. Accessed February 12, 2014. 6. Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. American journal of obstetrics and gynecology 2007;196(2):147.e1 8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17306659. Accesse d February 17, 2014. 7. Dunn MS, Kaempf J, De Klerk A, et al. Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 2011;128(5):e1069 76. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22025591. Ac cessed December 8, 2013. 8. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet J M, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. The New England journal of medicine 2008;358(7):700 8. Available at: http://www.ncbi.nlm.nih.gov/pubme d/18272893. Accessed December 8, 2013. 9. Finer NN, Carlo WA, Walsh MC, et al. Early CPAP versus surfactant in extremely preterm infants. The New England journal of medicine 2010;362(21):1970 9. Available at: http://www.pubmedcentral.nih.gov/articlerender .fcgi?artid=3071534&tool=pmcentrez&re ndertype=abstract. Accessed December 8, 2013. 10. Davis PG, Lemyre B, De Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm

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26 neonates a fter extubation. The Cochrane database of systematic reviews 2001;(3):CD003212. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11687052. Accessed December 3, 2013. 11. Kamholz KL, Dukhovny D, Kirpalani H, et al. Economic evaluation alongside the Premature Infants in Need of Transfusion randomised controlled trial. Archives of disease in childhood. Fetal and neonatal edition 2012;97(2):F93 8. Available at: http://www .ncbi.nlm.nih.gov/pubmed/21733926. Accessed September 30, 2013. 12. CANSIM: Consumer Price Index for Canada. Available at: http://www5.statcan.gc.ca/subject sujet/result resultat.action?pid=3956&id=2178&lang=eng&type=ARRAY&pageNum=1&more=0. Accessed Februa ry 17, 2014. 13. United States Department of Labor. Consumer Price Index for the United States. Available at: http://www.bls.gov/cpi/. Accessed February 17, 2014. 14. Consumer Price Index for UK. Available at: http://www.statisticsauthority.gov.uk/. Access ed February 17, 2014. of a controlled trial of indomethacin prophylaxis for patent ductus arteriosus in premature infants. Early human development 2006;82(2):97 103. Ava ilable at: http://www.ncbi.nlm.nih.gov/pubmed/16469456. Accessed February 17, 2014. 16. Dukhovny D, Lorch S a, Schmidt B, et al. Economic evaluation of caffeine for apnea of prematurity. Pediatrics 2011;127(1):e146 55. Available at: http://www.ncbi.nlm.ni h.gov/pubmed/21173002. Accessed March 5, 2013. 17. Glick H, Doshi J, Sonnad S, Polsky D. Economic Evaluation in Clinical Trials New York, New York: Oxford Press; 2007. 18. Ramsey S, Willke R, Briggs A, et al. Good research practices for cost effectiveness analysis alongside clinical trials: the ISPOR RCT CEA Task Force report. Value in Research 8(5):521 33. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16176491. Access ed February 14, 2014. significance: issues in the design and analysis of stochastic cost effectiveness studies in health care. Medical care 1994;32(2):150 63. Available at: http://w ww.ncbi.nlm.nih.gov/pubmed/8302107. Accessed January 24, 2014. 20. Lee S, Anderson L. BC Perinatal Services Costing Project: Report on Costs in the NEonatal Intensive Care Unit Vancouver, BC, Canada; 2004.

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27 21. Zupancic JAF, Hibbs AM, Palermo L, et al. Eco nomic evaluation of inhaled nitric oxide in preterm infants undergoing mechanical ventilation. Pediatrics 2009;124(5):1325 32. Available at: http://pediatrics.aappublications.org/cgi/doi/10.1542/peds.114.2.417. Accessed April 29, 2013. 22. Tretiak R, Laup acis A, Rivire M, McKerracher K, Soutre E. Cost of allogeneic and autologous blood transfusion in Canada. Canadian Cost of Transfusion Study Group. canadienne 1996;154(10):1 501 8. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1487839&tool=pmcentrez&re ndertype=abstract. Accessed February 17, 2014. 23. Centers for Medicare & Medicaid Services Physician Fee Schedule Search. 24. Ontario Health Insurance, Schedule of Benefits. 2013. 25. Rivero Arias O, Gray A. The multinational nature of cost effectiveness analyses alongside multinational clinical trials. Society for Pharmacoeconomics and Outcomes Research 13(1):34 41. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20667068. Accessed February 17, 2014.

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28 BIOGRAPHICAL SKETCH Meredith Mowitz received her medical degree from The University of Vermont in 2007. After completing her pediatric residency (2007 2010) she was selected to remain as chief pediatric resident at the University of Florida (2010 2011) She then went on to complete her neonatology fellowship at the University of Florida while earning her Master of Science in Clinical and Translational Science, both completed in 2014.