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Probiotics reduce mortality Should parents of eligible infants be offered routine probiotics? William Odita Tarnow-Mordi WINNER.

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Presentation on theme: "Probiotics reduce mortality Should parents of eligible infants be offered routine probiotics? William Odita Tarnow-Mordi WINNER."— Presentation transcript:

1 Probiotics reduce mortality Should parents of eligible infants be offered routine probiotics? William Odita Tarnow-Mordi 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: decision making is based on three fundamentals:- patients' circumstances best research evidence patients' preferences

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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.” 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? edicine/bmj/nnf5/pdfs/comment/pro b_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.

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, 2007 Editor: James Lind Library “Would any of you have agreed to participate in a placebo controlled trial of prophylactic antibiotics for colorectal surgery after 1975?”

19 Reduction of perioperative deaths by antibiotic prophylaxis for colorectal surgery

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

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 1.To identify the optimum regimen - ? 2.To refute evidence of lower mortality or morbidity - ? 3.Better estimates of specific products’ efficacy - ? 4.Pooling RCTs of different products is unacceptable - ? 5.Better estimates of short and long term risk - ? 6.The current meta analysis shows heterogeneity - X 7.Access to a rigorously tested probiotic will assist clinicians to gain familiarity and experience - √ 8.Many clinicians remain substantially uncertain - √

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 < ) for mortality in Deshpande’s 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

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; 3: No Probiotics Probiotics P value n NEC85 (6.6%)37 (3.0%)< NEC- related Death 35 (2.7%)14 (2.2%)< 0.005

39 Annual hospital charges associated with NEC in the US $290 – 772 million assuming 2, ,463 cases of NEC in US annually (1, 2) $100,000 per case (1, 3) $173,000 per case (4) (1)Russell RB et al, Pediatrics 2007; 120: e1 (2)Holman RC et al. Ped Perinat Epidemiol. 2006; 20: (3)Christensen RD et al. Fetal Pediatr Pathol. 2010; 29: (4)Bisquera JA, et al. Pediatrics. 2002; 109:

40 J A Stockman III Editor: Yearbook of Pediatrics ‘One could not fault individual centres from proceeding with probiotics use until more data becomes available’ Yearbook of Pediatrics 2009;

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; 76:F Costeloe KL, et al. Pediatr Res. 2004; 55:2802 (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; 312:

43 4. Pooling RCTs of different products is unacceptable - ? Pooling is accepted in Cochrane Reviews of antibiotics, β 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 < 1.0 and confidence intervals overlap. I 2 = 0.

46 7. Access to probiotics may help clinicians gain experience and confidence - √ 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 - √ 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

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 < 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 Chalmers Editor, 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 Issue Response Comment Pooling RCTs of different probiotics is unacceptable ? Pooling is accepted in Cochrane Reviews of antibiotics, β 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 Rationale for further placebo RCTs

66 Issue Response Comment Current meta analysis shows heterogeneity x There is no evidence of heterogeneity. Relative risks for mortality are < 1.0 and confidence intervals overlap. I 2 = 0. Access to probiotics may help clinicians gain experience √ 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 √ Should clinicians discuss the options with parents and let them decide? Rationale for further placebo RCTs

67

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 0.6–1.7 can easily be dissipated by future evidence – big swings are quite common.”

70

71 “With > 2000 patients... odds ratios (or Relative Risks) may still change by as much as to fold, but bigger swings have not been seen.”

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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 > 2.0.

75 Reduction in NEC in VLBW infants in a before-after cohort study in Japan Controls ( ) Probiotic ( ) P value n NEC 6 (2.6%)0 (0%)<0.01 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; 99:1135–1138 Prophylactic LGG Probiotic ‘on demand’ No probiotics P value 19 ⁄ 418 (4.6%) 18 ⁄ 1024 (1.8%) 61 ⁄ 1900 (3.2%)

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