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Probiotics reduce mortality Should parents of eligible infants be offered routine probiotics?

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Title: Probiotics reduce mortality Should parents of eligible infants be offered routine probiotics?


1
Probiotics reduce mortalityShould parents of
eligible infants be offered routine probiotics?
  • William Odita Tarnow-Mordi
  • williamtm_at_med.usyd.edu.au
  • WINNER Centre for Newborn Research, Westmead
    Hospital
  • NHMRC Clinical Trials Centre, University of Sydney

2
  • This presentation will discuss unapproved or
    investigational use of various probiotic
    preparations.
  • Professor Tarnow-Mordi has no commercial or
    financial relationship relating to this
    presentation.

3
The many researchers, clinicians and families
who have contributed to RCTs or systematic
reviews of probiotics in preterm infants deserve
great credit. Their work is sincerely
acknowledged.
4
Outline
  • Three current priorities
  • Evidence based medicine and patient preference
  • Parallels with antibiotics for colorectal surgery
  • Rationale for more placebo RCTs
  • What should parents be told?
  • Can we reach a consensus for global
    collaboration?

5
  • Three current priorities

6
  • Continue research on probiotics
  • Disclose to parents and Institutional Review
    Boards current evidence that probiotics halve
    mortality rates
  • Assess whether probiotics can be made more
    widely accessible in RCTs and cohort studies

7
  • Evidence based medicine and patient preference

8
Evidence based medicine Sackett et al, BMJ 1996
312 71-72
  • decision making is based on three
    fundamentals-
  • patients' circumstances
  • best research evidence
  • patients' preferences

9
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10
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11
Physicians' and patients' choices in evidence
based practice
  • the clinician must consider the patient's
    preferences and likely actions
  • Haynes RB, Deveraux PJ,
  • Guyatt GH. BMJ 2002 324 1350.

12
Howard Bauchner, 2010 Editor Journal Watch
Pediatrics and Adolescent Medicine
  • My suggestion is to discuss with parents the
    benefits, as well as arguments against routine
    probiotic use, and let them decide.
  • http//pediatrics.jwatch.org May 26, 2010

13
Edmund Hey (1934 2009) Editor Neonatal
Formulary 5
  • Do we, knowing what we now know, have the right
    to deny parents the option of giving a probiotic
    ...?
  • Hey, E. Comment Neonatal Formulary 5
  • Has the time come to start using probiotics more
    widely?
  • http//www.blackwellpublishing.com/medicine/bmj/nn
    f5/pdfs/comment/prob_com_jul09.pdf

14
Who is setting the agenda?
  • Parents preferences and options have received
    little attention so far.

15
The James Lind Alliance
  • to bring patients and clinicians together in
    'Priority Setting Partnerships' to identify and
    prioritise the unanswered questions that they
    agree are most important.
  • http//www.lindalliance.org

16
A key question
  • After each death without access to open label
    probiotic - particularly deaths from NEC - will
    clinicians, IRBs, managers and parents be
    satisfied that sufficient information and choices
    were given?

17
  • Parallels with antibiotics for colorectal
    surgery

18
Sir Iain Chalmers, 2007Editor James Lind Library
  • Would any of you have agreed to participate in
    a placebo controlled trial of prophylactic
    antibiotics for colorectal surgery after 1975?
  • http//www.crash2.lshtm.ac.uk/

19
Reduction of perioperative deaths by antibiotic
prophylaxis for colorectal surgery
20
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21
Antibiotic prophylaxis for colorectal surgeryLau
et al J Clin Epidemiol 1995
  • By 1975, 10 RCTs had been done in 603 patients
  • Cumulative meta analysis showed a 75 reduction
    in the odds of mortality

22
  • In the next 12 years, 11 more RCTs reported
    another 928 patients, with little change in the
    odds of death.
  • Half - over 450 - received no antibiotics.
  • On balance of probability, most deaths in these
    patients could be ascribed to that omission.

23
Antibiotic prophylaxis for colorectal surgery
Lau et al J Clin Epidemiol 1995
  • Trials of individual antibiotics had too few
    patients to show a significant result.
  • If the question is does antibacterial
    prophylaxis reduce mortality in colon surgery
    patients? pooling all antibiotic trials is
    entirely acceptable.

24
Antibiotic prophylaxis for colorectal surgeryLau
et al J Clin Epidemiol 1995
  • Withholding all antibiotics from control group
    patients is hardly justifiable if it is known
    from pooling of all antibiotic trials that
    lives are saved.

25
Antibiotic prophylaxis for colorectal surgery
Lau et al J Clin Epidemiol 1995
  • If the question is which antibiotic regimen is
    best ...?, placebo controlled trials will not
    provide a reliable answer.

26
Antibiotic prophylaxis for colorectal surgery
Lau et al J Clin Epidemiol 1995
  • For that, multiple treatment arm head to head
    RCTs are needed.
  • Placebo groups without antibiotics will not be
    ethically acceptable.

27
Two important differences
  • Antibiotics were routinely available for adults
    undergoing colorectal surgery and clinicians were
    experienced in using them.
  • Previously evaluated, locally approved probiotics
    are not yet routinely accessible for preterm
    infants in most jurisdictions.

28
  • As probiotics become more widely available,
    parallels with antibiotic prophylaxis in
    colorectal surgery will become closer.

29
  • Rationale for further placebo RCTs

30
Rationale for further placebo RCTs
  • To identify the optimum regimen - ?
  • To refute evidence of lower mortality or
    morbidity - ?
  • Better estimates of specific products efficacy -
    ?
  • Pooling RCTs of different products is
    unacceptable - ?
  • Better estimates of short and long term risk - ?
  • The current meta analysis shows heterogeneity - X
  • Access to a rigorously tested probiotic will
    assist clinicians to gain familiarity and
    experience - v
  • Many clinicians remain substantially uncertain -
    v

31
1. To identify the optimum regimen - ?
  • 2 arm placebo RCTs cannot reliably identify the
    optimum probiotic regimen.
  • This will require multiple arm RCTs

32
2. To refute evidence of lower mortality - ?
  • New RCTs are very unlikely to refute or nullify
    current evidence of lower mortality

33
What would it take to nullify the Relative Risk
Reduction of 0.42 (0.29 0.62, p lt 0.00001) for
mortality in Deshpandes systematic review?
34
  • It would need a change in Relative Risk of
  • 1/ 0.42 2.2 or more
  • i.e. more than double

35
  • This would require one of 2 scenarios-
  • (A) 2,000 new patients in RCTs showing the
    opposite effect on mortality, or
  • (B) 4,500 new patients in RCTs with RR 1.0

36
  • Given the substantial prior evidence from
  • (i) cohort studies
  • (ii) animal physiology
  • (iii) bench top research
  • scenarios (A) and (B) are very unlikely.

37




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38
Hoyos AB. 55 reduction in incidence of NEC
after probiotics
  • Before-after cohort study in a single NICU
  • L acidophilus B infantis 250 million each
    daily
  • Int J Infect Dis 1999 3197-202

1993-94 No Probiotics 1994-95 Probiotics P value
n 1282 1237
NEC 85 (6.6) 37 (3.0) lt0.0002
NEC-related Death 35 (2.7) 14 (2.2) lt 0.005
39
Annual hospital charges associated with NEC in
the US
  • 290 772 million
    assuming
  • 2,900 - 4,463 cases of NEC in US annually (1, 2)
  • 100,000 per case (1, 3)
  • 173,000 per case (4)
  • Russell RB et al, Pediatrics 2007 120 e1
  • Holman RC et al . Ped Perinat Epidemiol. 2006
    20 498-506.
  • Christensen RD et al. Fetal Pediatr Pathol. 2010
    29 185-98.
  • Bisquera JA, et al. Pediatrics. 2002 109 423-8.

40
J A Stockman IIIEditor Yearbook of Pediatrics
  • One could not fault individual centres from
    proceeding with probiotics use until more data
    becomes available
  • Yearbook of Pediatrics 2009441-443

41
3. Better estimates of efficacy - ?
  • Up to 35 of controls in RCTs may become
    colonised by probiotics.
  • The true effect of probiotics in reducing
    mortality may thus be underestimated by placebo
    RCTs.
  • Kitajima H, et al. Arch Dis Child Fetal
    Neonatal. 1997 76F101-7.
  • Costeloe KL, et al. Pediatr Res. 2004 552802
    (Pt 2802 Supp S).

42
3. Better estimates of efficacy - ?
  • Before-after cohort studies may enhance the
    validity of placebo RCTs by providing
    uncontaminated estimates of efficacy, without
    colonisation of prior controls
  • Black N. Why we need observational studies to
    evaluate the effectiveness of health care. BMJ.
    1996 3121215-8.

43
4. Pooling RCTs of different products is
unacceptable - ?
  • Pooling is accepted in Cochrane Reviews of
    antibiotics, ß blockers, tocolytics, calcium
    channel blockers, contraceptives, surfactants,
    hypothermia, ventilation, immunoglobulins and
    many others.

44
5. Better estimates of risk - ?
  • Potential risks of probiotics, such as sepsis,
    allergy, antibiotic resistance are important.
  • But these must be balanced against current
    evidence showing a substantial increase in
    mortality in controls.
  • Large cohort/ Phase IV studies may estimate risks
    more reliably than RCTs

45
6. The current meta analysis suffers from
heterogeneity - x
  • There is no evidence of heterogeneity.
  • Relative risks for mortality in all RCTs are lt
    1.0 and confidence intervals overlap.
  • I2 0.

46
7. Access to probiotics may help clinicians gain
experience and confidence - v
  • But only half the infants will get probiotics in
    RCTs.
  • Special access schemes or non randomised
    prospective cohort or case-control studies could
    allow the option of access for all eligible
    infants.

47
8. Many clinicians remain substantially
uncertain about the evidence - v
  • If so, a RCT is an appropriate option for those
    clinicians.
  • However, clinicians may also wish
  • to ensure access to probiotics for eligible
    infants
  • discuss the options with parents and let them
    decide.

48
  • What should parents be told?

49
  • Parents cannot exercise informed consent and
    choice - whether in RCTs or cohort studies of
    routinely offered probiotics - without
    transparent information.

50
  • Information should be given in as much detail as
    for a placebo RCT no double standard
  • Probiotic use would ideally be within a
    prospectively planned cohort study or RCT in a
    local or national or international network of
    NICUs

51
Key points for parents
  • In randomized studies in over 2000 preterm
    babies, those given probiotics were half as
    likely to die or to get necrotizing enterocolitis
    (a severe gut disease).

52
Key points for parents
  • There was no increase in adverse effects, but
    these are still possible, particularly in the
    smallest infants.

53
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54
  • Can we reach a consensus for global
    collaboration?

55
Should placebo RCTs continue?
  • YES
  • If clinicians are unconvinced by the evidence,
  • or
  • If the only access to a previously evaluated
    probiotic product, shown to be effective in an
    earlier RCT, is through a placebo RCT
  • and
  • If parents are fully informed and give consent

56
Can a previously evaluated probiotic be made
available by a special access scheme?
  • YES - in certain jurisdictions, with
  • Drug and Therapeutics Committee or IRB/ Executive
    approval
  • A reputable supplier of a previously evaluated
    probiotic produced according to stringent
    guidelines for Good Manufacturing Practice
  • Quality control by an accredited food standards
    laboratory with
  • random checks of each batch for extraneous
    pathogens
  • confirmation of colonisation in stools
  • Detailed information to parents and their
    informed consent

57
Options for clinicians and parents
  • Those not convinced may wish to support ongoing
    placebo RCTs
  • Those who are convinced may wish to use a
    previously evaluated probiotic (e.g. Bin Nun et
    al, 2005 or Lin et al, 2008) in previously
    published doses, after informed parental consent,
    and preferably in a prospectively planned cohort
    study within a local or national network or
    registry

58
Danish Cohort Study of probiotic prophylaxis
  • Inception date March 2010
  • Infants lt 30 weeks gestation in centres in
    Denmark
  • Intervention L acidophilus, BB 12 (produced by
    Chr. Hansen company under EC Guidelines for Good
    Manufacturing Practice) offered to parents of
    eligible infants
  • Primary outcomes NEC, mortality

59
Other options for international RCTs
  • Multiple arm, head to head RCTs with no
    placebo

60
Other options for international RCTs
  • Cluster factorial RCTs in which individual NICUs
    are randomly allocated to use , for example, one
    of various probiotic regimens, started early vs
    late

61
A workshop on global clinical collaborative
probiotic research?
  • Appropriate as probiotics may be the most
    significant clinical advance in neonatology since
    surfactant
  • Important to seek representation from
  • Parent liaison groups
  • Drug regulatory and food standard agencies
  • International collaborative NICU networks
  • Bio-ethicists
  • Bio-statisticians, trialists, epidemiologists

62
Sir Iain ChalmersEditor, James Lind Library
  • Current attitudes to, and restrictions on,
    therapeutic research are powerful disincentives
    to people who wish to confront uncertainties
    about the effects of treatments.
  • It is up to clinicians, patients, and the public
    in general to decide whether they wish to
    continue tolerating this bizarre state of
    affairs.
  • Chalmers I. BMJ 2008 337 a841

63
  • Appendices

64
Rationale for further placebo RCTs
Issue Response Comment
Identify the optimum regimen ? 2 arm placebo RCTs cannot reliably identify the optimum regimen. This requires multiple arm RCTs
Confirm? mortality ? New RCTs are very unlikely to nullify current evidence of lower mortality
Better estimates of efficacy ? Placebo RCTs may underestimate efficacy if there is contamination of controls. Before-after cohort studies may add independent validity through uncontaminated estimates of efficacy.
65
Rationale for further placebo RCTs
Issue Response Comment
Pooling RCTs of different probiotics is unacceptable ? Pooling is accepted in Cochrane Reviews of antibiotics, ß blockers, tocolytics, surfactants, ventilation immunoglobulins and many others.
Better estimates of short or long term risk ? Potential risks of probiotics must be balanced against the substantially increased risk of mortality in controls. Large cohort/ Phase IV studies may estimate risks more reliably than RCTs
66
Rationale for further placebo RCTs
Issue Response Comment
Current meta analysis shows heterogeneity x There is no evidence of heterogeneity. Relative risks for mortality are lt 1.0 and confidence intervals overlap. I2 0.
Access to probiotics may help clinicians gain experience v But only half the infants get probiotics in RCTs. Special access schemes cohort studies allow access for all infants.
Clinicians remain substantially uncertain about the evidence v Should clinicians discuss the options with parents and let them decide?
67
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68
Ioannidis and Lau, PNAS 2001
  • Analysed cumulative meta analyses of 45
    different treatments in perinatal medicine.
  • Looked at how often there were big swings in the
    odds ratio for a treatment after a new trial was
    added to the analysis

69
  • With 500 randomized patients, odds ratios in
    the range of 0.61.7 can easily be dissipated by
    future evidence big swings are quite common.

70
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71
  • With gt 2000 patients ... odds ratios (or
    Relative Risks) may still change by as much as
    0.74- to 1.35-fold, but bigger swings have not
    been seen.

72
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73
  • Current evidence of lower mortality is very
    unlikely to be nullified by more placebo RCTs.

74
  • Cumulative meta-analyses of Magnesium Sulphate
    in Acute Myocardial Infarction and albumin in
    adult intensive care were shifted to the null by
    RCTs of 58,050 and 6,997. Neither was associated
    with a swing in odds ratio of gt 2.0.

75
Reduction in NEC in VLBW infants in a
before-after cohort study in Japan
Controls (1994 - 98) Probiotic (1999 - 03) P value
n 226 338
NEC 6 (2.6) 0 (0) lt0.01
Death 38 (16.8) 39 (11.5) NS
Satoh Y et al Int J Pro and Prebiotics 2007
76
Increased NEC in VLBW infants associated with
probiotic in Finland over 12 years
  • Incidence was highest in NICU using prophylactic
    Lactobacillus Rhamnosus GG 6 billion per day
  • No before-after comparison
  • Luoto R, et al. Acta Paediatrica 2010
    9911351138

Prophylactic LGG Probiotic on demand No probiotics P value
19 / 418 (4.6) 18 / 1024 (1.8) 61 / 1900 (3.2) 0.0090
77
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