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Nitric Oxide in the Preterm: systematic reviews

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Title: Nitric Oxide in the Preterm: systematic reviews


1
Nitric Oxide in the Preterm systematic reviews
  • Keith J Barrington
  • CHU Sainte Justine
  • Montréal
  • Canada

2
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

3
Death before discharge
4
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.

5
BPD among survivors
6
Death or BPD
7
Survival without bronchopulmonary dysplasia
  • Early rescue treatment studies no apparent
    benefit
  • subgroup analysis of Van Meurs et al reduction in
    infants gt 1 kg birthweight.
  • Early routine treatment modest and almost
    significant reduction in the combined outcome of
    death or BPD RR 0.93, 95 CI 0.86 1.01.
  • Heterogeneity I2 34, Kinsella EUNO no
    benefit.
  • Subgroup analysis of Kinsella suggested lower
    risk infants (BW gt1000 g) had a benefit.
  • In Schreiber, subgroup analysis suggested only
    the less sick infants (OI less than the median)
    benefited.

8
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, (1st 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 7- 14 d, less severe disease
    may increase chance of benefit.

9
Severe IVH or PVL
10
Brain Injury
  • Early rescue studies no significant effect, the
    direction of the difference is toward increased
    serious IVH
  • Not significant at plt0.05, 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 I2 80

11
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?

12
Neurodevelopmental impairment
13
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 n566
  • Conclusions are substantially unchanged

14
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

15
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

16
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

17
MAPPiNO
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
18
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

19
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

20
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

21
Siblings clusters
Distribution of multiplesby treatment group Distribution of multiplesby treatment group
Trial n multiples iNO Placebo
Van Meurs 2005 22 4.9 10 (45.5) 12 (54.5)
Srisuparp 2002 2 5.9 0 (0.0) 2 ( 100)
Kinsella 2006 130 16.4 61 (46.9) 69 (53.1)
Hascoet 2005 14 9.7 10 (71.4) 4 (28.6)
Schreiber 2003 26 12.6 11 (42.3) 15 (57.7)
Kinsella 1999 2 2.4 1 (50.0) 1 (50.0)
Dani 2006 2 5.0 2 ( 100) 0 (0.0)
EUNO 2008 152 19.0 71 (46.7) 81 (53.3)
Ballard 2006 84 14.4 47 (56.0) 37 (44.0)
OVERALL 434 13.1 213 (49) 221 (51)
22
Primary endpoints
  • Death or chronic lung disease (CLD) using best
    available definition
  • (alive and O2 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)

Main endpoints assessable for all patients
(patients with no event were censored)
23
Primary endpoint 1
Death or CLD (Best available definition)
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)
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)
RR (95 CI)
Trial
Kinsella 1999
0.99 (0.81, 1.21)
Srisuparp 2002
1.59 (0.55, 4.62)
Schreiber 2003
0.77 (0.57, 1.04)
Hascoet 2005
1.11 (0.85, 1.43)
INNOVO 2005
0.93 (0.82, 1.07)
Van Meurs 2005
0.98 (0.88, 1.09)
Kinsella 2006
0.99 (0.91, 1.08)
Dani 2006
0.53 (0.19, 1.46)
Ballard 2006
0.85 (0.74, 0.98)
EUNO 2008
1.01 (0.83, 1.23)
OVERALL
0.96 (0.91, 1.01) p0.095
0.2
0.5
1
2
5
Favours placebo
Favours iNO
24
Primary endpoint 2
25
Primary endpoint 2a
Severe Neurological Event (including death)
RR (95 CI)
iNO Placebo
Trial
Subhedar 1997
11 / 20 (55)
8 / 22 (36)
1.51 (0.77, 2.99)
Kinsella 1999
27 / 48 (56)
22 / 32 (69)
0.82 (0.58, 1.16)
Srisuparp 2002
3 / 16 (19)
5 / 18 (28)
0.64 (0.18, 2.24)
Schreiber 2003
27 / 105 (26)
40 / 102 (39)
0.66 (0.43, 1.01)
Hascoet 2005
42 / 61 (69)
36 / 84 (43)
1.61 (1.18, 2.20)
INNOVO 2005
36 / 64 (56)
41 / 62 (66)
0.85 (0.64, 1.13)
Van Meurs 2005
143 / 224 (64)
128 / 225 (57)
1.13 (0.97, 1.31)
Kinsella 2006
170 / 398 (43)
171 / 395 (43)
1.01 (0.86, 1.19)
Dani 2006
10 / 20 (50)
8 / 20 (40)
1.25 (0.62, 2.50)
EUNO 2008
110 / 399 (28)
92 / 401 (23)
1.22 (0.95, 1.57)
Ballard 2006
22 / 294 (7)
21 / 288 (7)
1.03 (0.58, 1.83)
OVERALL
601 / 1649 (36)
572 / 1649 (35)
1.06 (0.98, 1.16) p0.149
0.1
0.2
0.5
1
2
5
Favours placebo
Favours iNO
26
Secondary endpoint 1
27
Secondary endpoint 3
28
Secondary endpoint 4
This analysis assumes that if IVH is missing then
IVH 0 for on study results.
Severe intra-ventricular hemorrhage
29
Secondary endpoint 4a
Severe intra-ventricular hemorrhage worse than
baseline IVH
RR (95 CI)
iNO Placebo
Trial
INNOVO 2005
0.65 (0.11, 3.73)
2 / 64 (3)
3 / 62 (5)
Kinsella 2006
0.78 (0.55, 1.11)
49 / 398 (12)
63 / 394 (16)
Hascoet 2005
1.02 (0.35, 2.96)
9 / 51 (18)
5 / 24 (21)
Schreiber 2003
0.37 (0.16, 0.88)
6 / 26 (23)
8 / 13 (62)

Dani 2006
1.23 (0.13, 11.48)
2 / 14 (14)
1 / 8 (13)
EUNO 2008
1.26 (0.81, 1.94)
43 / 300 (14)
36 / 309 (12)
OVERALL
0.87 (0.68, 1.12) p0.29
111 / 853 (13)
116 / 810 (14)

0.2
0.5
1
2
5
10
0.1
30
Secondary endpoint 4a
Severe intra-ventricular hemorrhage adjusted for
worse baseline HUS result
RR (95 CI)
iNO Placebo
Trial
INNOVO 2005
1 / 35 (3)
2 / 28 (7)
0.40 (0.04, 4.01)
Kinsella 2006
60 / 360 (17)
74 / 348 (21)
0.83 (0.63, 1.09)
Hascoet 2005
12 / 53 (23)
6 / 25 (24)
1.06 (0.47, 2.42)
Schreiber 2003
6 / 26 (23)
8 / 13 (62)
0.23 (0.08, 0.62)

Dani 2006
3 / 14 (21)
1 / 8 (13)
2.31 (0.67, 7.95)
EUNO 2008
46 / 305 (15)
41 / 312 (13)
1.10 (0.74, 1.63)
OVERALL
128 / 793 (16)
132 / 734 (18)
0.87 (0.71, 1.08) p0.21

0.01
0.1
0.2
0.5
1
2
5
10
31
Subgroup Analyses(death or CLD)
32
Exposure subgroup analyses (Death or CLD)
Overall n () Overall n () 95 CI 95 CI
Subgroup Group iNO Placebo Relative Risk LCL UCL p P (heterogeneity)  
Trials with median Start dose gt5ppm lt5 ppm 732 / 1194 (61) 739 / 1199 (62) 1.00 0.94 1.06 0.889 lt0.001  
gt5 ppm 218 / 435 (50) 252 / 428 (59) 0.83 0.74 0.95 0.005  
Trials with median Start dose gt10ppm lt10 ppm 779 / 1319 (59) 803 / 1321 (61) 0.98 0.92 1.04 0.413 N.S.  
gt10 ppm 171 / 310 (55) 188 / 306 (61) 0.87 0.76 0.99 0.041  
Exposure to iNO (trial level) Low 353 / 522 (68) 372 / 525 (71) 0.95 0.87 1.04 0.254 N.S.  
High 597 / 1107 (54) 619 / 1102 (56) 0.96 0.89 1.03 0.216  
Exposure to iNO (individual level) lt105 ppmdays 247 / 452 (55) 252 / 467 (54) 1.03 0.92 1.16 0.564 N.S.  
gt105 ppmdays 344 / 639 (54) 363 / 617 (59) 0.89 0.82 0.98 0.014  
Data from Subhedar removed from these analyses as
zero cell counts caused model instability. Srisup
arp, 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 gt 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
N1000 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 subgrouptreatment effect
(N.S. non significant)
33
Sensitivity analyses GEE model
Overall n () Overall n () 95 CI 95 CI
Outcome iNO Placebo Relative Risk LCL UCL p value
Death or CLD 956 (59) 993 (61) 0.96 0.91 1.00 0.0610
Severe Neurological Event 337 (25) 312 (23) 1.11 0.98 1.27 0.1072
Death at any time 386 (23) 374 (23) 1.03 0.92 1.16 0.5916
Death by 36 weeks 350 (21) 336 (20) 1.05 0.93 1.19 0.4504
Death by discharge 383 (23) 366 (22) 1.05 0.93 1.17 0.4481
Severe IVH 234 (19) 221 (18) 1.04 0.88 1.23 0.6404
34
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.

35
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?

36
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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