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