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@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. decision making is based on three fundamentals:- patients' circumstances best research evidence patients' preferences Evidence based medicineSackett et al, BMJ 1996: 312: 71-72

11. “…the clinician must consider the patient's preferences and likely actions …” Haynes RB, Deveraux PJ, Guyatt GH. BMJ 2002; 324: 1350. Physicians' and patients' choices in evidence based practice

12. Howard Bauchner, 2010Editor: 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/nnf5/pdfs/comment/prob_com_jul09.pdf

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

15. TheJames Lind Alliance … to bringpatients 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

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 - √ • 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 < 0.00001) 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.

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; 3:197-202

39. Annual hospital charges associated with NEC in the US $290 – 772 millionassuming • 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 . PedPerinatEpidemiol. 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 2009;441-443

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; 76:F101-7. 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; 312:1215-8.

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 asubstantialincrease inmortality 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. • I2 = 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