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Keith J Barrington CHU Sainte Justine Montréal Canada

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The systematic review Update of the Cochrane Review 13 RCTs of iNO in preterm infants with respiratory disease Varying eligibility, age of use, indications, dose, duration. Decided Post Hoc to divide them into 3 groups Early rescue Late rescue Early routine treatment

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Death before discharge

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Mortality None of the individual trials show a statistically significant reduction. Meta-analysis of the first 2 trials of early routine use previously showed potential difference: which was marginally significant. Potentially important magnitude of effect, but the estimate lacked precision. Adding the data from the abstract of the EUNO trial: now no difference, RR 0.91 (95% CI 0.74, 1.11) The early rescue, and later treatment in infants at risk of BPD groups show no effect on mortality.

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BPD among survivors

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Death or BPD

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Survival without bronchopulmonary dysplasia Early rescue treatment studies: no apparent benefit subgroup analysis of Van Meurs et al reduction in infants > 1 kg birthweight. Early routine treatment: modest and almost significant reduction in the combined outcome of death or BPD RR 0.93, 95% CI Heterogeneity I 2 = 34%, Kinsella + EUNO: no benefit. Subgroup analysis of Kinsella suggested lower risk infants (BW >1000 g) had a benefit. In Schreiber, subgroup analysis suggested only the less sick infants (OI less than the median) benefited.

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Survival without bronchopulmonary dysplasia Ballard et al report: significant benefit of inhaled nitric in improving survival without BPD. However the figures given, 165/294 vs. 182/288 are not significant using RevMan to calculate RR. Difference due to use of multiple outputation as planned, a statistical way of correcting for possible coherence among multiples, (1 st of multiples to be eligible randomized, therefore entered as a cluster, should be analyzed as a cluster). Subgroup analysis: reduction in combined death or BPD when started at d, less severe disease may increase chance of benefit.

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Severe IVH or PVL

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Brain Injury Early rescue studies: no significant effect, the direction of the difference is toward increased serious IVH Not significant at p<0.05, BUT potential evidence of harm should always be taken seriously, especially when there is no evidence of benefit. Later entry based on BPD risk not expected to affect IVH incidence. With the addition of EUNO 2009, early routine use shows no effect on brain injury, either severe IVH or combined outcome of severe IVH or PVL. Heterogeneity I 2 = 80%

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Brain Injury Previous analysis suggested a potential benefit in the early routine treatment group EUNO had a higher baseline OI, but a lower mortality than the other early routine treatment trials, Do these characteristics explain the difference, or is it just chance?

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Neurodevelopmental impairment

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Sensitivity analysis I have performed a sensitivity analysis of the early rescue treatment studies, eliminating the studies with very early primary outcomes, the studies with potential crossover, and studies with very small samples Analyses including Innovo, Kinsella 1999, and Van Meurs 2005, total n=566 Conclusions are substantially unchanged

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Problems with the meta-analysis Great variation in study design Different eligibility criteria Postnatal age severity of illness criteria Different primary outcomes Variable duration of therapy Variable doses

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IPD meta-analysis The standard review and meta-analysis suggested that there might be significant benefits in certain groups of infants: But no clear indications for therapy were evident Dont want to miss benefits Nor potential harms In some groups of infants

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IPD meta-analysis Obtaining original information on all the enrolled subjects Allows: Intention to treat analysis Consistency of definitions (if enough information was collected) Analyses of subgroups across trials Identification of patient characteristics associated with positive or negative responses

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Meta Analysis of Preterm Patients on inhaled Nitric Oxide Collaboration Inhaled nitric oxide in preterm infants: a systematic review and individual patient data meta-analysis

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MAPPiNO aims/objectives To determine whether inhaled nitric oxide in preterm infants receiving assisted ventilation improves survival without morbidity, specifically without: – CLD – cerebral injury – retinal injury – long-term disability To determine whether the effects of inhaled nitric oxide differ according to the risk profile of the patient in terms of: – gestational age at birth – severity of illness – antenatal steroid use – postnatal age at the time of randomization – ventilation mode at randomization – administration of exogenous surfactant – inhaled nitric dosage and duration of nitric oxide administration

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Reasons for IPD in MAPPiNO determine whether certain patient or treatment characteristics may predict benefit from inhaled nitric oxide in the premature infants (patient- level subgroup analyses) define CLD the same way across trials aim to analyse all endpoints in all patients in all trials, to avoid biases associated with selective publication endpoints address additional research questions improve trial identification, interpretation & dissemination via collaborative approach

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Results: a general approach main analyses used log-binomial regression models adjusted for trial subgroup analyses used poisson regression models with robust error variance due to issues with model convergence endpoints between siblings from multiple births the primary analyses were adjusted for multiple births using the multiple outputation approach (1000 repetitions) sensitivity analysis: generalized estimating equations (GEE) used to analyse the two main endpoints of interest

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Siblings clusters Distribution of multiples by treatment group Trialn% multiplesiNOPlacebo Van Meurs (45.5%)12 (54.5%) Srisuparp (0.0%)2 ( 100%) Kinsella (46.9%)69 (53.1%) Hascoet (71.4%)4 (28.6%) Schreiber (42.3%)15 (57.7%) Kinsella (50.0%) Dani ( 100%)0 (0.0%) EUNO (46.7%)81 (53.3%) Ballard (56.0%)37 (44.0%) OVERALL (49%)221 (51%)

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Main endpoints assessable for all patients (patients with no event were censored) Primary endpoints Death or chronic lung disease (CLD) using best available definition (alive and O 2 dependent at 36 weeks PMA if calculable, or trialists own definition) Severe adverse neurological event after randomization (intracranial hemorrhage (IVH) grade III or IV, or cystic periventricular leukomalacia (PVL) or other pathologies such as periventricular echodensity, periventricularcysts, ventriculomegaly or hydrocephalus)

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Subhedar removed from the analysis as zero cell counts caused model instability. * χ 2 test for heterogeneity p > 0.05 Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method. Death or CLD (Best available definition) OVERALL* iNO 40 / 48 (83%) 6 / 16 (38%) 43 / 105 (41%) 42 / 61 (69%) 54 / 64 (84%) 170 / 224 (76%) 292 / 398 (73%) 4 / 20 (20%) 165 / 294 (56%) 134 / 399 (34%) 954 / 1629 (59%) RR (95% CI)Trial Placebo 27 / 32 (84%) 4 / 18 (22%) 56 / 102 (55%) 51 / 84 (61%) 56 / 62 (90%) 174 / 225 (77%) 294 / 395 (74%) 8 / 20 (40%) 184 / 288 (64%) 137 / 401 (34%) 992 / 1627 (61%) Favours placeboFavours iNO EUNO 2008 Ballard 2006 Dani 2006 Kinsella 2006 Van Meurs 2005 INNOVO 2005 Hascoet 2005 Schreiber 2003 Srisuparp 2002 Kinsella (0.91, 1.01) p= (0.83, 1.23) 0.85 (0.74, 0.98) 0.53 (0.19, 1.46) 0.99 (0.91, 1.08) 0.98 (0.88, 1.09) 0.93 (0.82, 1.07) 1.11 (0.85, 1.43) 0.77 (0.57, 1.04) 1.59 (0.55, 4.62) 0.99 (0.81, 1.21) Primary endpoint 1

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Primary endpoint 2 OVERALL* RR (95% CI) Trial Severe Neurological Event Data from Ballard not available for this analysis. * χ 2 test for heterogeneity p > / 20 (5%) 8 / 48 (17%) 1 / 16 (6%) 16 / 105 (15%) 31 / 61 (51%) 5 / 64 (8%) 69 / 224 (31%) 117 / 398 (29%) 8 / 20 (40%) 81 / 399 (20%) 315 / 1649 (19%) 3 / 22 (14%) 7 / 32 (22%) 4 / 18 (22%) 25 / 102 (25%) 28 / 84 (33%) 6 / 62 (10%) 52 / 225 (23%) 112 / 395 (28%) 7 / 20 (35%) 68 / 401 (17%) 286 / 1649 (17%) Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method. Favours placebo Favours iNO 1.12 (0.98, 1.29) p= (0.88, 1.61) 1.13 (0.50, 2.52) 1.04 (0.83, 1.30) 1.35 (0.99, 1.83) 0.81 (0.26, 2.51) 1.57 (1.06, 2.34) 0.63 (0.35, 1.13) 0.27 (0.03, 2.13) 0.76 (0.31, 1.88) 0.37 (0.04, 3.25) EUNO Dani 2006 Kinsella 2006 Van Meurs 2005 INNOVO 2005 Hascoet 2005 Schreiber 2003 Srisuparp 2002 Kinsella 1999 Subhedar 1997 iNO Placebo

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Primary endpoint 2a Data on deaths only available from Ballard. * χ 2 test for heterogeneity p=0.050 Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method. Severe Neurological Event (including death) RR (95% CI) Trial iNO Placebo OVERALL* Ballard 2006 EUNO 2008 Dani 2006 Kinsella 2006 Van Meurs 2005 INNOVO 2005 Hascoet 2005 Schreiber 2003 Srisuparp 2002 Kinsella 1999 Subhedar / 20 (55%) 27 / 48 (56%) 3 / 16 (19%) 27 / 105 (26%) 42 / 61 (69%) 36 / 64 (56%) 143 / 224 (64%) 170 / 398 (43%) 10 / 20 (50%) 110 / 399 (28%) 22 / 294 (7%) 601 / 1649 (36%) 8 / 22 (36%) 22 / 32 (69%) 5 / 18 (28%) 40 / 102 (39%) 36 / 84 (43%) 41 / 62 (66%) 128 / 225 (57%) 171 / 395 (43%) 8 / 20 (40%) 92 / 401 (23%) 21 / 288 (7%) 572 / 1649 (35%) (0.98, 1.16) p= (0.58, 1.83) 1.22 (0.95, 1.57) 1.25 (0.62, 2.50) 1.01 (0.86, 1.19) 1.13 (0.97, 1.31) 0.85 (0.64, 1.13) 1.61 (1.18, 2.20) 0.66 (0.43, 1.01) 0.64 (0.18, 2.24) 0.82 (0.58, 1.16) 1.51 (0.77, 2.99) Favours placebo Favours iNO

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* χ 2 test for heterogeneity p > 0.05 Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method. OVERALL* iNO 11 / 20 (55%) 22 / 48 (46%) 2 / 16 (13%) 16 / 105 (15%) 28 / 61 (46%) 33 / 64 (52%) 114 / 224 (51%) 78 / 398 (20%) 4 / 20 (20%) 22 / 294 (7%) 54 / 399 (14%) 384 / 1649 (23%) Trial Death at any time Placebo 7 / 22 (32%) 17 / 32 (53%) 2 / 18 (11%) 22 / 102 (22%) 25 / 84 (30%) 36 / 62 (58%) 102 / 225 (45%) 94 / 395 (24%) 6 / 20 (30%) 21 / 288 (7%) 41 / 401 (10%) 373 / 1649 (23%) Favours placeboFavours iNO EUNO 2008 Ballard 2006 Dani 2006 Kinsella 2006 Van Meurs 2005 INNOVO 2005 Hascoet 2005 Schreiber 2003 Srisuparp 2002 Kinsella 1999 Subhedar (0.93, 1.17) p= (0.95, 2.09) 1.03 (0.58, 1.83) 0.70 (0.23, 2.10) 0.85 (0.65, 1.11) 1.13 (0.93, 1.37) 0.89 (0.65, 1.22) 1.53 (0.98, 2.39) 0.72 (0.39, 1.33) 1.06 (0.17, 6.67) 0.86 (0.55, 1.36) 1.73 (0.83, 3.58) RR (95% CI) Secondary endpoint 1

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* χ 2 test for heterogeneity p > 0.05 Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method. OVERALL* iNO 10 / 20 (50%) 22 / 48 (46%) 2 / 16 (13%) 15 / 105 (14%) 28 / 61 (46%) 32 / 64 (50%) 114 / 224 (51%) 78 / 398 (20%) 4 / 20 (20%) 22 / 294 (7%) 54 / 399 (14%) 381 / 1649 (23%) Trial Death before discharge Placebo 7 / 22 (32%) 17 / 32 (53%) 2 / 18 (11%) 20 / 102 (20%) 25 / 84 (30%) 36 / 62 (58%) 97 / 225 (43%) 93 / 395 (24%) 6 / 20 (30%) 21 / 288 (7%) 41 / 401 (10%) 365 / 1649 (22%) Favours placeboFavours iNO EUNO 2008 Ballard 2006 Dani 2006 Kinsella 2006 Van Meurs 2005 INNOVO 2005 Hascoet 2005 Schreiber 2003 Srisuparp 2002 Kinsella 1999 Subhedar RR (95% CI) 1.06 (0.94, 1.19) p= (0.95, 2.09) 1.03 (0.58, 1.83) 0.70 (0.23, 2.10) 0.86 (0.65, 1.13) 1.19 (0.97, 1.46) 0.86 (0.62, 1.19) 1.53 (0.98, 2.39) 0.75 (0.39, 1.43) 1.06 (0.17, 6.67) 0.86 (0.55, 1.36) 1.57 (0.74, 3.34) Secondary endpoint 3

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Severe intra-ventricular hemorrhage Secondary endpoint 4 Data from Ballard not available for this analysis. * χ 2 test for heterogeneity p > 0.05 Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method. Subhedar removed from the analysis as zero cell counts caused model instability. RR (95% CI) Trial iNO Placebo Favours iNO 0.01 OVERALL* EUNO 2008 Dani 2006 Kinsella 2006 Van Meurs 2005 INNOVO 2005 Hascoet 2005 Schreiber 2003 Srisuparp 2002 Kinsella / 47 (6%) 1 / 6 (17%) 13 / 105 (12%) 14 / 61 (23%) 2 / 41 (5%) 67 / 189 (35%) 60 / 398 (15%) 3 / 18 (17%) 71 / 399 (18%) 234 / 1264 (19%) 2 / 30 (7%) 3 / 5 (60%) 19 / 102 (19%) 14 / 83 (17%) 3 / 32 (9%) 46 /164 (28%) 74 / 395 (19%) 4 / 19 (21%) 56 / 401 (14%) 221 / 1231 (18%) (0.88, 1.23) p= (0.91, 1.77) 0.84 (0.22, 3.22) 0.81 (0.59, 1.12) 1.26 (0.93, 1.73) 0.52 (0.09, 2.93) 1.39 (0.70, 2.78) 0.67 (0.34, 1.33) 0.28 (0.04, 1.91) 0.95 (0.17, 5.36) Favours placebo This analysis assumes that if IVH is missing then IVH = 0 for on study results.

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Data from Van Meurs, Srispuarp, Subhedar, Kinsella 99 and Ballard not available for this analysis. * χ 2 test for heterogeneity p > 0.05 Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method. Data have been removed where Baseline HUS was taken after start of study gas and also where baseline HUS showed the presence of a Grade 4 IVH Severe intra-ventricular hemorrhage worse than baseline IVH RR (95% CI) Trial iNO Placebo Secondary endpoint 4a OVERALL0.87 (0.68, 1.12) p=0.29 EUNO (0.81, 1.94) Dani (0.13, 11.48) Schreiber (0.16, 0.88) Hascoet (0.35, 2.96) Kinsella (0.55, 1.11) INNOVO (0.11, 3.73) 2 / 64 (3%)3 / 62 (5%) 49 / 398 (12%)63 / 394 (16%) 9 / 51 (18%)5 / 24 (21%) 6 / 26 (23%)8 / 13 (62%) 2 / 14 (14%)1 / 8 (13%) 43 / 300 (14%)36 / 309 (12%) 111 / 853 (13%)116 / 810 (14%) 0.1

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Data from Van Meurs, Srispuarp, Subhedar, Kinsella 99 and Ballard not available for this analysis. * χ 2 test for heterogeneity p > 0.05 Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method. Data have been removed where Baseline HUS was taken after start of study gas Severe intra-ventricular hemorrhage adjusted for worse baseline HUS result RR (95% CI) Trial iNO Placebo Secondary endpoint 4a OVERALL EUNO 2008 Dani 2006 Schreiber 2003 Hascoet 2005 Kinsella 2006 INNOVO / 35 (3%)2 / 28 (7%) 60 / 360 (17%)74 / 348 (21%) 12 / 53 (23%)6 / 25 (24%) 6 / 26 (23%)8 / 13 (62%) 3 / 14 (21%)1 / 8 (13%) 46 / 305 (15%)41 / 312 (13%) 128 / 793 (16%)132 / 734 (18%) (0.71, 1.08) p= (0.74, 1.63) 2.31 (0.67, 7.95) 0.23 (0.08, 0.62) 1.06 (0.47, 2.42) 0.83 (0.63, 1.09) 0.40 (0.04, 4.01)

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Subgroup Analyses (death or CLD)

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Exposure subgroup analyses (Death or CLD) Overall n (%)95% CI SubgroupGroupiNOPlacebo Relative RiskLCLUCLp P (heterogeneity)* Trials with median Start dose >5ppm<=5 ppm732 / 1194 (61%)739 / 1199 (62%) <0.001 >5 ppm218 / 435 (50%)252 / 428 (59%) Trials with median Start dose >10ppm<=10 ppm779 / 1319 (59%)803 / 1321 (61%) N.S. >10 ppm171 / 310 (55%)188 / 306 (61%) Exposure to iNO (trial level) Low353 / 522 (68%)372 / 525 (71%) N.S. High597 / 1107 (54%)619 / 1102 (56%) Exposure to iNO (individual level)<105 ppm*days247 / 452 (55%)252 / 467 (54%) N.S. >=105 ppm*days344 / 639 (54%)363 / 617 (59%) Data from Subhedar removed from these analyses as zero cell counts caused model instability. Srisuparp, Kinsella 2006, EUNO 2008 and Ballard classified as high exposure trials, others classified as low exposure. High exposure was defined as area under the dose-time curve >= 70 calculated on a trial specific basis. Per-patient exposure analysis only included three trials (Kinsella 06, EUNO 2008 and Ballard). All other trials were excluded either because dose exposure was dependent on response (INNOVO, Van Meurs, Subhedar, Srisuparp, Hascoet and Kinsella99) or because data on length of time on treatment was not available (Dani, Schreiber). (These data were not initially requested). Exposure was calculated as AUC and patients were grouped as less than the median (105) or not. Estimates derived from N=1000 iterations of a poisson regression model with robust error variance using multiple outputation method. * p value for heterogeneity was calculated as the proportion of the 1000 models which had non-significant p values for the interaction term for subgroup*treatment effect (N.S. = non significant)

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Sensitivity analyses – GEE model Overall n (%)95% CI OutcomeiNOPlaceboRelative RiskLCLUCLp value Death or CLD956 (59%)993 (61%) Severe Neurological Event337 (25%)312 (23%) Death at any time386 (23%)374 (23%) Death by 36 weeks350 (21%)336 (20%) Death by discharge383 (23%)366 (22%) Severe IVH234 (19%)221 (18%)

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Implications Further analysis of individual patient data will allow definition of patient characteristics most promising for future studies, and most promising treatment protocols, including dose and duration. Based on a single high quality study, later prolonged treatment with iNO seems to decrease BPD among at-risk infants, without adverse effects, The benefit of early routine treatment which appeared possible after 2 trials were completed now seems less likely after EUNO, further analysis of the IPD may help to clarify.

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Unanswered questions Preterm infants with clear evidence of PPHN exist, is it reasonable to withhold iNO based on these analyses? There were 142 babies with pulmonary hypertension in the database, with a small non-significant improvement in the primary outcome Diagnostic criteria for PPHN in these infants are uncertain Infants with acute deterioration after the early neonatal period, improvements in oxygenation may follow iNO, such babies were not eligible for the majority of these studies. Does iNO improve their survival or long term outcomes?

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Implications for further research Most promising appears to be infants at high risk for BPD who are still intubated at 7 days of age Treatment should be prolonged and commence at more than 5 ppm

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