Evidence for clinical interventions:
how do probiotics measure up?
Dan Merenstein, MDDirector of Research Family Medicine
Associate Professor of Family MedicineGeorgetown University
Full Disclosure
• Dannon, Sanofi, and Pharmavite have
provided Georgetown funding for separate
clinical trials or consulting
• I have been a scientific expert about
marketing claims for a probiotic product for
Bayer and Procter & Gamble
Goals• Discuss a few probiotic treatments that are
well proven
– These are examples; many others not discussed
• Use traditional treatments as comparisons
• Challenge views of outcomes and
presentation of data
Established Medical Literature
• Reviewed NEJM articles
• There were 3 research articles in weekly
issue
• I will use them as examples of expectations
NEJM-1
• Observational studies for three decades
suggest that subclinical thyroid disease
during pregnancy is associated with adverse
cognitive outcomes for children
– Some medical groups recommend testing and
treatment
• Treatment for subclinical thyroid diseases in
two large RCTs did not result in better
cognitive outcomes in children through 5
years of age compared to no treatment for
subclinical hypothyroidism
NEJM-2
• A humanized antibody against interleukin-
31 receptor A, in the treatment of atopic
dermatitis
• In the per protocol analysis 40% change
from highest dose to placebo
• Most of secondary outcomes very small
effect sizes
NEJM-3
• Blinatumomab (a bispecific monoclonal
antibody) or standard-of-care chemotherapy
for ALL
• Overall survival was significantly longer in
the blinatumomab group than in the
chemotherapy group-this is take home
message
• 7.7 months versus 4 months
Miscarriage and Caffeine
• Pregnant women are discouraged from coffee
during pregnancy
• “Caffeine Miscarriage” to google you get,
“Women who consumed 200 milligrams or
more of caffeine each day (about two cups of
regular coffee or five 12-ounce cans of
caffeinated soda) had twice the miscarriage
risk as those who didn't have any.”
Abstract Direct Quote
An increasing dose of daily caffeine intake during
pregnancy was associated with an increased risk
of miscarriage, compared with no caffeine intake,
with an adjusted hazard ratio (aHR) of 1.42
(95% confidence interval 0.93 to 2.15)
Number Needed to Treat
• Statins for MI for one year=100-427
• Vitamin D for hip fractures=50
• Antibiotics for sinusitis=15
• Aspirin for CV protection=40
• Imitrex for migraine=2.6
• Probiotics to treating colic=4
• Probiotics for preventing AAD in
pediatrics=9
• Probiotics for NEC=41
Influenza Vaccine 16-65 year olds
• 90 reports containing 116 data sets
– 69 clinical trials of over 70,000 people
– 27 comparative cohort studies (about eight million
people)
– 20 case-control studies (nearly 25,000 people)
• Overall effectiveness of influenza-like illness;
NNT = 40 (26, 128)
• Overall efficacy of preventing confirmed
influenza; NNT = 71 (64, 80)
Jefferson T, et al. Vaccines for preventing influenza in healthy adults. Cochrane
Database Syst Rev. 2014 Mar 13;(3).
Influenza Treatment Drugs• Review of 107 studies, 20 of oseltamivir (9623
participants)
• For the treatment of adults, oseltamivir reduced
the time to first alleviation of symptoms by 16.8
hours (8.4, 25.1)
• This represents a reduction in the time to first
alleviation of symptoms from 7 to 6.3 days
• NNT=36
• Oseltamivir increases the risk of adverse effects,
such as nausea (NNH=28), vomiting(NNH=22)
Jefferson T, et al. Neuraminidase inhibitors for preventing and treating influenza
in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr 10;(4).
Probiotics and Acute Infectious
Diarrhea• Review of 63 randomized controlled trials (56/63
in infants and children) of 8,014 subjects with
proven or presumed infectious diarrhea
• Administration of a probiotic agent decreased the
mean duration of diarrhea by 24.7 hours (95% CI
15.9 – 33.6 hours)
Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute
infectious diarrhoea. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD003048.
Review. PMID: 21069673.
Probiotics and URIs• 20 studies included in review
• Average decrease in illness duration was 0.5-1 day
in those who took probiotics vs placebo.
King S, et al. Br J Nutr. 2014 Jul 14;112(1):41-54.
Where Is the Evidence for The Impressive
Statement about Mammogram
“Reduces Their Risk Of Dying From Breast Cancer
By 20%”?
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Nystrom L. et al. Long-term effects of mammography screening: updated overview of
the Swedish randomised trial. Lancet 2002; 359:909-919
But What Is The
Absolute Risk Reduction?
Of 117,260 women who do not undergo mammography
about 584 (0.5%) will die of breast cancer, whereas out
of 129,750 women who do undergo mammography 511
(0.4%) will die of breast cancer.
Relative Risk Reduction = |(0.4 – 0.5)|/0.5) = 0.2 = 20%
Absolute Risk Reduction = |(0.4 – 0.5)| = 0.1 = 0.1%
Number Needed to Treat = 1/0.001 = 1000
Interpretation: 1,000 women must undergo biennial
mammography for 12 years to prevent one breast
cancer death 17
UC Meta-analysis of VSL#3
• 3 low risk of bias studies with 319 patients met the
inclusion criteria
• Remission in 44.6% of the VSL#3 patients versus
25.1% of placebo
• RRR=78%
• ARR=19.5%
• NNT=4, (5,10)
Mardini HE and Grigorian AY. Probiotic mix VSL#3 is effective adjunctive
therapy for mild to moderately active ulcerative colitis: a meta-analysis.
Inflamm Bowel Dis. 2014 Sep;20(9):1562-7.
FMT, where is the evidence?
• 7562 original articles, not studies, about FMT
• AEs 28.5% of the time
• 3, yes THREE, CDI RCTs– One fresh vs. frozen stools-enema
– One via-nasoduodenal tube
– One in C. Diff-colonoscopy, 91% vs 63% of placebo
showed improvement, 46 total patients
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Cochrane Pediatric AAD
• The incidence of AAD in the probiotic group was
8% (163/1992)
• Control group 19% (364/1906)
Relative Risk Reduction = |(0.08 – 0.19)|/0.19) = 0.58 =
58%
Absolute Risk Reduction = |(0.08 – 0.19)| = 0.11 = 11%
Number Needed to Treat = 1/0.11 = 9 (8,12)
Goldenberg JZ, PMID: 26695080
20
Cochrane C. Diff
• A total of 31 trials (4492 participants), 11 studies
were rated as a high risk of bias due mostly to missing
outcome data.
Relative Risk Reduction = |(5.5 – 2.0)|/5.5) = 0.64 = 64%
Absolute Risk Reduction = 3.5%
Number Needed to Treat = 28
Conclusion: Based on this systematic review and meta-analysis of 23
randomized controlled trials including 4213 patients, moderate quality
evidence suggests that probiotics are both safe and effective for preventing
Clostridium difficile-associated diarrhea
Goldenberg JZ, et al. PMID: 2372865821
Colic
• L. reuteri DSM 17938
• Four double-blind RCTs involving 345 infants with colic
(174 probiotic, 171 placebo)
• Decreased crying -25.4 minutes [95% CI: -47.3, -3.5]
• In breastfed 28% success vs. 9%, NNT 4
• No AEs reported in any trials
Sung et al. Lactobacillus reuteri DSM 17938 is effective in breastfed infants with colic: an
individual participant data meta-analysis, Under Review
Cochrane NEC Review
• 20 studies, 5,529 infants
• Reduce incidence of severe NEC; RR=0.43, (0.33,
0.56); NNT=30
• Death; RR=0.65, (0.52, 0.81); NNT=41
• Our updated review of available evidence strongly
supports a change in practice. Head to head
comparative studies are required to assess the
most effective preparations, timing, and length of
therapy to be utilized.
AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm
infants. Cochrane Database Syst Rev. 2014 Apr 10;(4)
Cochrane Mammogram
To help ensure that the women are fully informed
before they decide whether or not to attend
screening, we have written an evidence-based leaflet
for lay people that is available in several languages
on www.cochrane.dk. Because of substantial
advances in treatment and greater breast cancer
awareness since the trials were carried out, it is
likely that the absolute effect of screening today is
smaller than in the trials. Recent observational
studies show more overdiagnosis than in the trials
and very little or no reduction in the incidence of
advanced cancers with screening.
A Tipping Point?
• 156% increase in probiotic usage in the U.S. in last 10
years, p value trend=0.03
• “Not all supplements, of course, lack evidence of efficacy.
Many supplements, including vitamins, minerals, and
probiotics, are important components of modern health
care.”
• “BOTTOM LINE Moderate-quality evidence suggests that
probiotics are associated with lower rates of antibiotic-
associated diarrhea in children (aged 1 month to 18 years)
without an increase in adverse events.”
JAMA October 11, 2016 Volume 316, Number 14
Board Review Question
• Cramping abdominal pain is the most
common symptom along with diarrhea,
constipation, or alternating diarrhea and
constipation. The goals of treatment are
symptom relief and improved quality of life.
Probiotics appear to improve symptoms.
Use Recommendation ReferencePediatric
mild UC
European Society for Paediatric Gastroenterology,
Hepatology and Nutrition (ESPGHAN) -
probiotics for children with mild ulcerative colitis
when standard therapy isn’t working
Turner et al.
2012. JPGN
AAD ESPGHAN - probiotics in prevention of pediatric AAD.
L. rhamnosus GG or S. boulardiiCanani et al.
2016
Acute
pediatric
gastro-
enteritis
ESPGHAN - probiotics in the management of
acute gastroenteritis in children
Piescik-Lech
et al. 2013.
Allergy
prevention
World Allergy Organization recommends
probiotics for allergy prevention in pregnant and
breast-feeding mothers at high risk of having an
allergic child and in infants at high risk of
developing allergic disease
Fiocchi et al.
2015. World
Allergy
Organ J
Recommendations of probiotics from global
medical organizations or authorities
World Gastroenterology
Organisation
www.worldgastroenterology.org/guidelines/global-guidelines/probiotics-and-
prebiotics
Take Home Points
• The data are there for probiotics
• Have realistic expectations; conduct and review
studies as such– NEJM study 4 vs 7 months
• Small changes are often important, especially if
costs are low and AEs not very significant
• Probiotics aren’t the flu shot, but neither is the flu
shot
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